Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ijpharm.2023.122617

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jddst.2022.104122

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Brick dust molecules are usually poorly soluble in water and lipoidal components, making it difficult to formulate them in dosage forms that provide efficient pharmacological effects. A co-amorphous system is an effective strategy to resolve these issues. However, their glass transition temperatures (Tg) are relatively lower than those of polymeric amorphous solid dispersions, suggesting the instability of the co-amorphous system. This study aimed to formulate a stable co-amorphous system for brick dust molecules by utilizing sodium taurocholate (NaTC) with a higher Tg. A novel neuropeptide Y5 receptor antagonist (AntiY5R) and NaTC with Tg of 155 °C were used as the brick dust model and coformer, respectively. Ball milling formed a co-amorphous system for AntiY5R and NaTC (AntiY5R-NaTC) at various molar ratios. Deviation from the theoretical Tg value and peak shifts in Fourier-transform infrared spectroscopy indicated intermolecular interactions between AntiY5R and NaTC. AntiY5R-NaTC at equal molar ratios resulting in an 8.5-fold increase in AntiY5R solubility over its crystalline form. The co-amorphous system remained amorphous for 1 month at 25 °C and 40 °C. These results suggest that the co-amorphous system formed by utilizing NaTC as a coformer could stably maintain the amorphous state and enhance the solubility of brick dust molecules.

DOI： 10.3390/pharmaceutics15010084

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Previously, we reported that the combined use of spermine (SPM) and sodium taurocholate (STC) (SPM-STC) significantly improves the oral absorption of rebamipide (BCS class IV) and pulmonary absorption of interferon-α without any harmful histopathological changes in the gastrointestinal tract and lungs, respectively. In the present study, we examined the effect of SPM-STC on the transport of fluorescein isothiocyanate-labeled dextrans (FDs) across Caco-2 cell monolayers and attempted to clarify the mechanisms underlying the transport enhancement caused by SPM-STC. SPM-STC were found to significantly enhance the transport of FDs, while the treatment with SPM-STC was not harmful, and the decrease in transepithelial electrical resistance was transient and reversible. The voltage-clamp study clearly indicated that the opening of the paracellular route could be mainly responsible for the enhanced transport of FD-4. As for the mechanisms, it was found that SPM-STC caused a significant increase in membrane fluidity, which would lead to the enhanced transport of small-molecule drugs such as rebamipide. Since SPM-STC increased intracellular Ca2+ via Ca2+ uptake through Ca2+ channels and Ca2+ release from the endoplasmic reticulum stimulated by the IP3 pathway, the subsequent possible activation of the MLCK signaling pathway would have led to the contraction of the actin-myosin ring. The rearrangement of tight junction-constituting proteins induced through the MAPK pathway has also been suggested as a possible mechanism for opening tight junctions. Claudin-4, a key protein constituting the tight junction, merged with F-actin along with the plasma membrane, was significantly decreased, which would be at least partial structural evidence for the tight-junction opening.

DOI： 10.1016/j.ejpb.2022.10.020

PubMed

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s11095-022-03337-4

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Other Link： https://link.springer.com/article/10.1007/s11095-022-03337-4/fulltext.html

Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s11095-022-03325-8

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Other Link： https://link.springer.com/article/10.1007/s11095-022-03325-8/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ijpharm.2022.121904

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ejpb.2022.02.002

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Authorship：Corresponding author  

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ejpb.2021.08.013

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.xphs.2021.09.014

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Among drugs in development and/or in market, there are poorly water-soluble and poorly lipid-soluble compounds. Rebamipide, classified into BCS class IV, is one of those drugs which provide very low bioavailability and/or the difficulty of formulation for oral administration. Because of its low solubility in available lipoidal excipients, it was impossible to prepare an adequate SNEDDS formulation of rebamipide. Then, we tried to increase the solubility of rebamipide in lipoidal excipients for preparing a more practical SNEDDS formulation by making the complex with its counter ion, tetrabutylphosphonium hydroxide (TBPOH) or NaOH. Rebamipide concentration in ethanol was proportionally increased with the increment of TBPOH or NaOH added, indicating that the formation of complex with a counter ion should contribute to the solubilization of rebamipide in ethanol. Both Rebamipide-TBPOH complex (Reb-TBPOH) and Rebamipide-NaOH complex (Reb-NaOH) obtained by lyophilization showed no endothermic peak in DSC and no diffraction peak in XRPD, suggesting that the solid state of both complexes should be amorphous. Reb-TBPOH maintained the dissolution of rebamipide in SNEDDS vehicle (Capryol 90:Cremophor EL:Transcutol P = 4:3:3) at 20 mg/g at least for 28 days, while Reb-NaOH did it at 10 mg/g. In vitro dissolution study showed that Reb-TBPOH SNEDDS and Reb-NaOH SNEDDS containing rebamipide at 10 mg/g maintained the complete dissolution of rebamipide in FaSSIF (intestinal luminal condition). In the gastric luminal condition (pH3.9 acetate buffer), the high concentration, close to the complete dissolution, was transiently observed and quickly decreased to one-sixth of the maximum, but it was still around 70 times higher than that of the crystalline powder. The additional utilization of Eudragit EPO for SNEDDS preparations of both complexes successfully maintained the high concentrations of rebamipide in the gastric luminal condition. In vivo oral absorption studies clearly indicated that SNEDDS preparations utilizing Reb-counter ion complex successfully improved rebamipide absorption.

DOI： 10.1016/j.ejps.2021.105721

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

The improvement effect of the combined use of spermine (SPM), a polyamine, with sodium taurocholate (STC) on the pulmonary drug absorption was investigated utilizing poorly absorbable drugs with various molecular sizes in rats. The pulmonary absorption of rebamipide, a low molecular but poorly absorbable drug after oral administration, was significantly improved by the combined use of SPM with STC (SPM-STC formulation), while poly- L-lysine did not show a significant change in rebamipide absorption from the lungs. Furthermore, the safety of the SPM-STC formulation for the lungs was assessed in rats by the histopathological study and any local toxicity was not observed while poly-L-lysine, a typical chemical causing the toxicity for the epithelial cells, provided several histopathological changes. In addition, the SPM-STC formulation significantly improved the pulmonary absorption of fluorescein isothiocyanate dextran 4 (FD-4, Mw ca 4000) and interferon-α (IFN-α, Mw ca 25,000) as well. Our present results clearly indicated that the SPM-STC formulation significantly improved the pulmonary absorption of poorly absorbable small and large molecular drugs without any harmful effects on the lungs. Therefore, the SPM-STC formulation would be a useful one for the pulmonary absorption of drugs, specifically macromolecular ones, which are very difficult to be absorbed after oral administration.

DOI： 10.1016/j.xphs.2021.06.015

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Language：Japanese   Publisher：(公社)日本薬剤学会  

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Language：Japanese   Publisher：(公社)日本薬剤学会  

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1186/s41182-019-0167-4

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Other Link： http://link.springer.com/article/10.1186/s41182-019-0167-4/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

Nasal drug delivery has attracted significant attention as an alternative route to deliver drugs having poor bioavailability. Large-molecule drugs, such as peptides and central nervous system drugs, would benefit from intranasal delivery. Drug absorption after intranasal application depends on the nasal retention of the drug, which is determined by the nasal mucociliary clearance. Mucociliary clearance (MC) is an important determinant of the rate and extent of nasal drug absorption. The aim of the present study was to clarify the effect of the changes in MC on in vivo drug absorption after nasal application, and to justify the pharmacokinetic model to which the MC parameter was introduced, to enable prediction of bioavailability after intranasal administration. The pharmacokinetics of norfloxacin (NFX) after intranasal administration were evaluated following the modification of nasal MC by pretreatment with the MC inhibitors propranolol and atropine and the MC enhancers terbutaline and acetylcholine chloride. From the relationship between nasal MC and bioavailability after nasal application, prediction of drug absorption was attempted on the basis of our pharmacokinetic model. Propranolol and atropine enhanced the bioavailability of NFX by 90 and 40%, respectively, while the bioavailability decreased by 30% following terbutaline and 40% following acetylcholine chloride. As a result of changes in the MC function, nasal drug absorption was changed depending on the nasal residence time of the drug. On the basis of our pharmacokinetic model, the nasal drug absorption can be precisely predicted, even when the MC is changed. This prediction system allows the quantitative evaluation of changes in drug absorption due to changes in nasal MC and is expected to contribute greatly to the development of nasal formulations.

DOI： 10.1021/acs.molpharmaceut.8b00464

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Drug absorption after nasal application is dependent on drug clearance from the nasal cavity, which is determined by nasal mucociliary clearance (MC). We previously developed an in vitro method to evaluate MC via the translocation velocity of fluorescent microspheres (V-FMS) applied to excised rat nasal mucosa. In the present study, the relationship between in vivo nasal MC and in vitro V-FMS was examined to optimize our PK model for the prediction of nasal drug absorption. Appropriate inhibitors (propranolol and atropine) and enhancers (terbutaline and acetylcholine chloride) of MC were utilized to modify MC. In vivo clearance of drug from the nasal cavity was determined from the disappearance of fluorescent microspheres (FMS) from the nasal cavity following nasal application to rats. The first order elimination rate constant, k(mc), was determined from the disappearance profiles of FMS. k(mc) was decreased to 35.8% by propranolol and 52.6% by atropine, but increased to 117% by terbutaline and 168% by acetylcholine chloride. A significant linear correlation was observed between k(mc) and V-FMS (r(2) = 0.9745, p < 0.001). These results indicate that in vivo k(mc) can be estimated from the in vitro parameter, V-FMS. By introducing linear correlation into our PK model, nasal drug absorption may be precisely estimated, even with changes in MC.

DOI： 10.1016/j.ejps.2018.01.032

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1541/ieejsmas.138.394

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

ObjectivesWe aimed to prepare a once-daily modified-release oral formulation of tacrolimus by utilizing an extended-release granules (ERG).
MethodsExtended-release granules were prepared using ethylcellulose (EC), hydroxypropylmethylcellulose (HPMC) and lactose via a solvent evaporation method with ethanol. Physicochemical and biopharmaceutical studies were performed to determine the formulation with optimum release profile of tacrolimus from ERG.
Key findingsTacrolimus existed in an amorphous state in ERG. Tacrolimus release from ERG was attenuated by EC and facilitated by lactose, suggesting that drug release kinetics could adequately be regulated by these components. Those release profiles were consistent with Higuchi's equation, suggesting a diffusion-type release mechanism. Smooth surface of ERG changed to the structure with pores after the release test, likely derived from the dissolution of HPMC and lactose. But ERG structure formed by EC was still maintained after the release test, leading to the longer maintenance of diffusion-type release. Two ERG formulations selected by blood concentration simulation successfully provided long-term retention of tacrolimus in blood in a human absorption study.
ConclusionsWe successfully developed the formulation exhibiting a significant reduction in C-max, the longer mean residence time and AUC close to that of an immediate-release tacrolimus formulation, being preferred from the viewpoint of safe and effective immunosuppressant pharmacotherapy.

DOI： 10.1111/jphp.12804

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Authorship：Last author   Language：English   Publisher：PHARMACEUTICAL SOC JAPAN  

Photodynamic therapy (PDT) is an emerging cancer treatment that uses photosensitizers (PS), along with light to activate them, resulting in oxidation of various biological components in cancer tissues. However, since most potential PS are solubilized and given as aqueous solution, PS is non-specifically distributed in the body, leading to the induction of various side effects in normal tissues that are exposed to daylight such as skin and eyes. To overcome the problem associated with non-specific in vivo disposition of PS, various approaches have been applied to develop safer dosage forms for PS with more efficient tumor delivery and lower disposition to normal tissues. Passive drug targeting to tumors with nanoparticulate formulations has been recognized as one of the potentially useful approaches to improve the poor tissue specificity of conventional cancer chemotherapy and this approach should also be applicable for more efficient tumor delivery of PS. In this review article, several issues concerning the efficacy of PDT using nanoparticle-based formulations are discussed and our recent attempts to temporally enhance the vascular permeability within tumors with photodynamic-treatment for the better therapeutic outcome of nanoparticle-based therapy are introduced.

DOI： 10.1248/cpb.c17-00063

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

To develop a safer and more potent paclitaxel (PTX) formulation, we prepared various oil-in-water emulsions by using egg phosphatidylcholine, Tween 80, and a mixture of triglycerides with different fatty acid chain lengths as the cosurfactant, surfactant, and oil phase component, respectively. The mean particle diameters of the PTX-emulsions prepared were around 100 nm. The PTX-emulsions did not provoke histamine release from rat mast cells and did not show any significant hemolytic activity, suggesting that PTX-emulsions are biocompatible. In vivo antitumor activity after single intraperitoneal injection of PTX-emulsions to ascites tumor-bearing mice revealed that the formulation containing tricaproin and triacetin ( 3: 1, wt/wt, PTX-emulsion B) significantly prolonged the survival time and suppressed the accumulation of ascites fluid. Two distinct in vitro release studies showed that the release of PTX from emulsion B was significantly faster than those from other preparations. These results indicate that the adequately sustained PTX release would lead to potent in vivo antitumor activity and that PTX-emulsion B would offer an alternative approach to treat peritoneal dissemination. (C) 2017 American Pharmacists Association((R)). Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.xphs.2016.12.029

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Authorship：Last author   Language：English   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.ijantimicag.2016.10.004

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Context: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable.
Objective: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach.
Method: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs. Results: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation.
Conclusion: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis.

DOI： 10.1080/1354750X.2016.1252958

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Three different nonionic surfactants (Brij 72, Span 20 and Tween 60) were used to prepare various naked and PEG niosomes. In-vivo study demonstrated that PEGylation dramatically increased the AUC and decreased the affinity to the liver of Brij 72 and Span 20 niosomes in rats. Liver perfusion experiments suggested that the hepatic uptake of naked Brij 72 and Span 20 niosomes could mainly be ascribed to the receptor-mediated uptake, while PEGylation of these niosomes could diminish the receptor-mediated hepatic disposition. Evaluation of serum proteins associated with niosomes revealed that PEGylation of these niosomes significantly reduced the association of serum proteins with them, including typical opsonins such as IgG and C3. On the other hand, in the case of Tween 60 niosomes, naked Tween 60 niosome showed large AUC and its PEGylation did not show any additional effect on the in-vivo pharmacokinetics. Furthermore, PEGylation of Tween 60 niosome did not significantly affect the hepatic disposition or the association of serum proteins with Tween 60 niosome. These results demonstrated that niosomes would exhibit distinct in-vivo disposition characteristics depending on the physicochemical properties of surfactants used and that PEGylation of niosomes with adequate compositions would be a powerful tool to improve their in-vivo behavior. (C) 2016 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2016.08.058

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

ObjectivesTacrolimus is a poorly water-soluble compound that is used to prevent allograft rejection. We aimed to prepare an extended release formulation of tacrolimus to achieve both an extended release profile and improved solubility of tacrolimus.
MethodsExtended release granules (ERG) of tacrolimus were prepared with lactose, ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) via the solvent evaporation method.
Key findingsIn an in vitro release study, ERG had an extended release profile, and the release rate of tacrolimus was regulated by the quantity of lactose, EC and HPMC in the formulation. HPMC-containing ERG successfully enhanced and maintained supersaturation of tacrolimus even after 24 h in a supersaturated release study. In contrast, the extent of supersaturation rapidly decreased after 4 h and the concentration nearly reached the same level as that of crystalline tacrolimus at 24 h for ERG without HPMC. In vivo absorption characteristics were compared between ERGs and immediate release (IR) formulation of tacrolimus. Successful and sustained absorption of tacrolimus without reducing bioavailability compared with IR formulation was observed for ERG.
ConclusionsThese results suggest the feasibility of combining an EC-based formulation with solid dispersion utilizing HPMC for the extended release of oral formulations and sustained absorption of tacrolimus.

DOI： 10.1111/jphp.12515

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To develop potent and safer formulation of photosensitizer for cancer photodynamic therapy (PDT), we tried to formulate hydrophobic porphyrin derivative, photoprotoporphyrin IX dimethyl ester (PppIX-DME), into polymeric nanoparticles composed of polyethylene glycol and polylactic acid block copolymer (PN-Por). The mean particle size of PN-Por prepared was around 80 nm and the zeta potential was determined to be weakly negative. In vitro phototoxicity study for PN-Por clearly indicated the significant phototoxicity of PN-Por for three types of tumor cells tested (Colon-26 carcinoma (C26), B16BL6 melanoma and Lewis lung cancer cells) in the PppIX-DME concentration-dependent fashion. Furthermore, it was suggested that the release of PppIX-DME from PN-Por would gradually occur to provide the sustained release of PppIX-DME. In vivo pharmacokinetics of PN-Por after intravenous administration was evaluated in C26 tumor-bearing mice, and PN-Por exhibited low affinity to the liver and spleen and was therefore retained in the blood circulation for a long time, leading to the efficient tumor disposition of PN-Por. Furthermore, significant and highly effective anti-tumor effect was confirmed in C26 tumor-bearing mice with the local light irradiation onto C26 tumor tissues after PN-Por injection. These findings indicate the potency of PN-Por for the development of more efficient PDT-based cancer treatments. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejps.2015.11.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

In this study, the data of 113 human bioequivalence (BE). studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between 20 Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P-eff). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P-eff might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P-eef/DO (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P-eff/Do &lt; 0.149 X 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are identified as risk factors for high intrasubject variability in oral drug absorption. This information is of importance to design the human BE study for oral drug products containing APIs with a risk of large intrasubject variability in oral absorption.

DOI： 10.1021/acs.molpharmaceut.5b00602

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Authorship：Corresponding author   Language：English   Publisher：SPRINGER/PLENUM PUBLISHERS  

Purpose The objective of this study was to improve the absorption behavior of N-251, a novel antimalarial drug, by preparing an appropriate self-nanoemulsifying drug delivery system (SNEDDS).
Methods Two different types of SNEDDS formulations, medium-chain fatty acid-based SNEDDS (MC-SNEDDS) and long-chain fatty acid-based SNEDDS (LC-SNEDDS), were prepared based on pseudo-ternary phase diagram, and examined for their in vivo oral absorption behavior in rats.
Results Oral dosing of MC-SNEDDS formulations significantly improved the bioavailability (BA) of N-251 compared with N-251 powders. However, its high hepatic extraction limited the BA of N-251 to only 0.49 for MC-SNEDDS B, the best formulation of MC-SNEDDS. LC-SNEDDS formulations, especially LC-SNEDDS F provided the highest BA, 0.65, and successfully attenuated the inter-individual difference in the absorption behavior. Furthermore, it was confirmed that lymphatic transport of N-251 for LC-SNEDDS F was significantly increased up to around 3.19 times larger than that for MC-SNEDDS B. Simulation study suggested that 20 to 39% of N-251 uptaken by the small intestine would be delivered to lymphatic system after oral administration of LC-SNEDDS F.
Conclusions SNEDDS formulations significantly improved the absorption behavior of N-251 and long-chain fatty acid-based lipid further improved it by avoiding the hepatic first-pass elimination.

DOI： 10.1007/s11095-015-1646-x

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Language：Japanese   Publisher：(公社)日本薬剤学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The effects of photo-triggered tumor vascular treatment (PVT) on the structural and functional properties of tumor vasculature were assessed in Colon-26 (C26) and B16/BL6 (B16) tumor-bearing mice. Furthermore, anti-tumor efficacy of subsequently injected PEG liposomal paclitaxel (PL-PTX) was also evaluated. As a photosensitizer, a hydrophobic porphyrin derivative was used and formulated in polymeric nanoparticle composed of polyethylene glycol-block-polylactic acid to avoid its non-specific in vivo disposition. In the mice bearing C26 with high permeable vasculature, the prominent anti-tumor activity was confirmed by PVT alone, but the subsequently injected PL-PTX did not show any additive effect. PVT itself initially induced apoptotic cell death of tumor vascular endothelial cells and platelet aggregation, which would have subsequently induced apoptosis of C26 tumor cells surrounding the vasculature. On the other hand, in the mice bearing B16 with low permeable vasculature, PVT enhanced the anti-tumor activity of subsequently injected PL-PTX, which would be attributed to the tumor disposition amount and area of PEG liposomes enhanced by PVT. These results clearly indicated that the treatment would have made it possible to provide more efficient extravasation of PL-PTX, leading to its more potent anti-tumor effect. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2014.12.038

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We tried to overcome the paclitaxel (PTX) resistance of cancer cells due to P-glycoprotein (P-gp) overexpression in the in vivo anti-tumor chemotherapy by utilizing polyethylene glycol-modified liposomal paclitaxel (PL-PTX). First of all, established were PTX-resistant Colon-26 cancer cells (C26/PTX) overexpressing P-gp, which provided IC50 value of PTX solution about 30 times larger than that obtained for control C26 (C26/control) in the in vitro MTT assay. Western blot analysis confirmed P-gp expression in C26/PTX 10 times higher than that in C26/control, indicating that the resistance acquisition of C26/PTX to PTX would be ascribed to the enhanced efflux of PTX by P-gp overexpressed in C26/PTX. However, the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice was similar to that in C26/control-bearing mice. Double immunohistochemical staining of vascular endothelial cells and apoptotic cells within tumor tissues demonstrated that the apoptotic cell death was preferentially observed in vascular endothelial cells in C26/PTX tumors after intravenous administration of PL-PTX, while that was in tumor cells in C26/control tumors. These results suggest that the in vivo anti-tumor effect of PL-PTX in C26/PTX-bearing mice would be ascribed to the cytotoxic action of PTX pumped out of tumor cells by overexpressed P-gp to vascular endothelial cells in tumor tissues. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejps.2014.06.009

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Angiogenesis, the sprouting of capillaries from preexisting ones, is essential for the sustained growth of solid tumors. In this study, we used SU5416, a hydrophobic molecule with potent tyrosine kinase inhibitor of type 2 receptor for vascular endothelial growth factor (VEGF), as PEGylated emulsion (SU5416-PE), and evaluated the antitumor potency of this formulation in Lewis lung cancer (LLC), Colon-26 (C26), and B16BL6 melanoma (B16) tumor-bearing mice. Intravenous injection of SU5416-PE into tumor-bearing mice significantly suppressed the growth of C26 and B16 tumors, but had no effect on the growth of LLC tumors. MTT assay revealed that SU5416 inhibited the proliferation of human umbilical vein endothelial cells in a concentration-dependent manner but did not show such an inhibitory effect on all types of tumor cells examined, demonstrating the specificity of SU5416 for endothelial cells. Considering that VEGF levels within C26 and B16 tumors were found to be about 10-fold and 20-fold higher than that in LLC tumors, respectively, it was suggested that SU5416-PE would inhibit angiogenesis in certain types of tumor tissue such as C26 and B16 where VEGF plays a major role for promoting angiogenesis, leading to the suppression of in vivo tumor growth. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2464-2469, 2014

DOI： 10.1002/jps.24071

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Language：Japanese   Publisher：日本DDS学会  

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Language：Japanese   Publisher：日本DDS学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER  

Background: Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract.
Objective: To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon.
Methods: The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using gamma-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters C-max, T-max after the capsule activation, AUC(0-24), and mean residence time were determined from the concentration time profiles.
Results: Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC(0-24) values revealed some site-specific absorption tendencies, the mean AUC(0-24) values obtained were similar regardless of the location of tacrolimus release from the capsule.
Conclusions: Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC(0-24), possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans. (C) 2014 Elsevier HS Journals, Inc. All rights reserved.

DOI： 10.1016/j.clinthera.2014.02.021

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Language：Japanese   Publisher：(公社)日本薬学会  

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Fruits and seeds of melinjo (Gnetum gnemon L.) are resveratrol derivative-rich materials. Pharmacokinetics of resveratrol derivatives in healthy volunteers after oral administration of 1000 mg of melinjo seed extract (MSE) powder were assessed and compared with those after oral dosing of trans-resveratrol (tRV) powder containing 4.8 mg of tRV only, equivalent to the content in 1000 mg MSE powder. Plasma tRV concentrations with enzymatic hydrolysis were maintained over 24 h, with a t(max) of 12 h and a mean residence time (MRT) of 14 h, 5 and 2 times higher than those for tRV powder intake, respectively. Gnetin C, a resveratrol dimer, with hydrolysis was maintained in plasma for &gt;96 h with a 36 h MRT. With repeated doses once daily for 28 days, plasma tRV and gnetin C concentrations with hydrolysis were in good agreement with the theoretical curves. MSE powder was well tolerated up to the oral dosing of 5000 mg with no serious adverse events.

DOI： 10.1021/jf4048435

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Vibrio vulnificus is a halophilic estuarine bacterium while it causes fatal septicemia or necrotizing wound infections in humans. This pathogen secretes the metalloprotease (V. vulnificus protease: VVP) and the cytolysin (V. vulnificus hemolysin: VVH) as protein toxins; however, their production was coordinated in response to the bacterial cell density. This regulation is termed quorum sensing (QS) and is mediated by the small diffusible molecule called autoinducer 2 (AI-2). In the present study, we investigated effects of disruption of luxO encoding a central response regulator of the QS circuit, as well as effects of temperature and growth phase, on the toxin production by V. vulnificus. Disruption of luxO was found to increase VVP production and expression of its gene vvpE. The expression of smcR, crp and rpoS, of which products positively regulate vvpE expression, and luxS encoding the AI-2 synthetase were also significantly increased. On the other hand, the luxO disruption resulted in reduction of VVH production and expression of its gene vvhA. Expression of other two genes affecting the QS circuit, luxT and rpoN, were also significantly decreased. The regulation systems of VVP production were found to exert their action during the stationary phase of the bacterial growth and to be operated strongly at 26 A degrees C. By contrast, those of VVH production apparently started at the log phase and were operated more effectively at 37 A degrees C.

DOI： 10.1007/s11274-013-1501-3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The aim of this study was to prepare a transdermal therapeutic formulation of CNS5161, an NMDA receptor antagonist developed as a drug for neuropathic pain. Since a silicone pressure-sensitive adhesive (PSA) was found to be the best PSA for CN55161 among six different PSAs examined in our previous study, the effects of the loading concentration of CNS5161 on release and rat skin permeability were investigated using silicone PSAs. The release of CNS5161 was elevated with an increase in the drug concentration from 1% to 14%. The transdermal flux at the steady state reached a plateau at 8% and over, while crystallization of CNS5161 was not observed for any formulation even at high drug concentrations. The drug concentration in rat skin at the steady state was also saturated at 8% and over, which correlated well with the transdermal flux at the steady state. Therefore, skin permeation clearance defined to the skin concentration at the steady state was almost constant at 0.2 1/h from 2% to 14% of CN55161, which suggests that drug concentrations in the skin would be a driving force for transport of the drug to the receptor side. Since increasing the concentration of CNS5161 in the PSA patch was not able to elevate the transdermal flux, 12 formulations containing several permeation enhancers were examined to improve the transdermal transport of CNS5161. Among them, the formulation containing propylene glycol, diisopropyl adipate, and polyvinylpyrrolidone significantly increased the transdermal flux by approximately 1.8-fold by improving the diffusivity of CNS5161 in the skin, and also significantly enhanced the analgesic effect of CNS5161. This formulation caused only slight skin irritation, which indicated that it would be a promising transdermal therapeutic system for CNS5161. (C) 2013 Elsevier B.V. All rights reserved..

DOI： 10.1016/j.ejps.2013.10.019

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Authorship：Last author  

DOI： 10.14843/jpstj.74.361

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Vibrio vulnificus is a ubiquitous estuarine microorganism but causes fatal systemic infections in cultured eels or shrimps, as well as in immunocompromised humans. An extracellular metalloprotease has been reported to be a potential virulence factor of the bacterium; however, a few strains isolated from a diseased eel or shrimp were recently found to produce a serine protease termed VvsA. In the present study, we first clarified the regulatory characteristics of the VvsA production in V. vulnificus strain NCIMB 2137, a metalloprotease-gene negative strain isolated from a diseased eel. V. vulnificus coordinates expression of virulence genes in response to the bacterial cell density, which is termed quorum sensing (QS) and is mediated by the small diffusible molecule called autoinducer 2 (AI-2). When cultivated at 26 degrees C, the vvsA expression was closely related with expression of the luxS gene encoding the synthase of the AI-2 precursor LuxS. Both VvsA and AI-2 were sufficiently secreted at early stationary phase of the bacterial growth. In contrast, when cultivated at 37 degrees C, far less amounts of the AI-2 and VvsA were produced even at the stationary phase. Disruption of the luxS gene was found to decrease significantly the vvsA expression and VvsA production. Disruption of luxO encoding the central response regulator of the QS circuit caused an increase in the vvsA expression and VvsA production at the logarithmic growth phase. These findings indicate that VvsA production is positively regulated by the V. vulnificus LuxS-dependent QS system, which operated more effectively at 26 degrees C than at 37 degrees C. (C) 2013 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.aquaculture.2013.09.041

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The aim of this study was to find out polymeric compounds that can inhibit the interaction between YM466, a novel anticoagulant, and bile to improve its oral bioavailability. In vitro ultrafiltration method using extract gall powder was useful to detect the formation of insoluble complex of YM466 with bile and also used to select a polymer that can inhibit the interaction between YM466 and bile. The in vitro studies revealed that aminoalkylmethacrylate (AAM) copolymer E, a polymethacrylate, dose-dependently inhibited the interaction between YM466 and bile and that this polymer could interact with bile salt, but not with YM466, possibly by electrostatic and/ or hydrophobic interactions. The coadministration of AAM copolymer E with YM466 to rats dose-dependently increased the plasma concentration of YM466 and it was found that the oral dose of the polymer three times of YM466 (polymer to drug ratio in weight, P-D ratio, 3) significantly increased AUC(0-1) h of YM466 to 2.6-fold of that of YM466 alone. Considering the condition of therapeutic use of YM466 and the maximum tolerated dose of the polymer, the formulation of P-D ratio 3 would be clinically practical and promising from the viewpoint of safety. (C) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association

DOI： 10.1002/jps.23484

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The objective of this study was to establish a novel prediction system of drug absorption in humans by utilizing human intestinal tissues. Based on the transport index (TI), a newly defined parameter, calculated by taking account of the change in drug concentrations because of precipitation on the apical side and the amounts accumulated in the tissue and transported to the basal side, the absorbability of drugs in rank order as well as the fraction of dose absorbed (Fa) in humans were estimated. Human intestinal tissues taken from ulcerative colitis or Crohn's disease patients were mounted in a mini-Ussing chamber and transport studies were performed to evaluate the permeation of drugs, including FD-4, a very low permeable marker, atenolol, a low permeable marker, and metoprolol, a high permeable marker. Although apparent permeability coefficients calculated by the conventional equation did not reflect human Fa values for FD-4, atenolol, and metoprolol, TI values were well correlated with Fa values, which are described by 100 [1 - e(- f (TI - ))]. Based on this equation, Fa values in humans for other test drugs were predicted successfully, indicating that our new system utilizing human intestinal tissues would be valuable for predicting oral drug absorption in humans. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2564-2571, 2013

DOI： 10.1002/jps.23609

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Mucociliary clearance (MC) is an important factor in determining nasal drug absorption and the ciliary beat of ciliated epithelial cells of the nasal mucosa is the driving force of MC. However, the relationship between MC and ciliary beat frequency (CBF) is still ambiguous. The purpose of this study was to establish an evaluation method of CBF as an index of mucociliary function and examine the relationship between MC and CBF. A sequence of images of ciliary beating of an excised rat nasal septum was captured using a high-speed digital video camera. CBF (beats per second, Hz) was determined from periodic changes in the contrast value of a specific location in a sequence of images. CBF under control conditions was 8.49+/-0.38Hz, which is similar to values reported for cultured human nasal epithelial cells and rat tracheal cells. beta-Adrenergic and cholinergic antagonists decreased CBF, while beta-adrenergic agonists and acetylcholine increased CBF. These results were similar with those observed for MC in our previous study. It was found that CBFs were significantly and linearly correlated with MC, indicating that MC is directly regulated by CBF and that this evaluation system allows the quantitative determination of nasal mucociliary function.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

There are many potential barriers to the effective delivery of small-molecule drugs to solid tumors. Most small-molecule chemotherapeutic drugs have a large volume of distribution upon intravenous administration, which is often associated with a narrow therapeutic index due to their high level of toxicity in healthy tissues. Nanoparticle-based therapeutics for tumor targeting have emerged as one of the promising approaches to overcome the lack of tissue specificity of conventional chemotherapeutic drugs. Various different concepts have been envisioned for nanoparticle-mediated drug targeting. Among them, the passive drug targeting strategy has been the most widely investigated, and numerous preclinical studies have provided insights into the validity of the strategy. This review article briefly introduces our recent findings related to the passive drug targeting strategy including its application in anti-angiogenic therapy, along with considerations to be taken into account and implications for the rational design of a passive drug targeting strategy.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The recently emerged concept of "vessel normalization" implies that judicious blockade of vascular endothelial growth factor (VEGF) signaling may transiently "normalize" the tumor vasculature, making it more suitable for tumor disposition of subsequently administered drugs. In this study, therefore, the effect of pretreatment with SU5416, a selective VEGF receptor-2 inhibitor, on tumor disposition and in vivo antitumor activity of polyethylene glycol (PEG)-modified liposomal paclitaxel (PL-PTX) was evaluated in Colon-26 solid tumor-bearing mice. To improve the solubility and in vivo disposition characteristics of SU5416, the inhibitor was formulated in PEGylated O/W emulsion (PE-SU5416). Pretreatment with PE-SU5416 significantly enhanced the in vivo antitumor effect of PL-PTX, although PE-SU5416 administration alone did not show any antitumor effect. Immunostaining for endothelial cells and pericytes demonstrated that the pretreatment with PE-SU5416 enhanced the pericyte coverage of the tumor vasculature. In addition, tumors treated with PE-SU5416 contained significantly smaller hypoxic regions compared with the nontreated control group, demonstrating that structural normalization of the tumor vasculature resulted in an improvement in tumor vessel functions, including oxygen supply. Furthermore, the pretreatment with PE-SU5416 increased the distribution of PEG liposomes and included PTX in the core region of the tumor, as well as conversely decreasing the ratio of their peripheral distribution. These results suggest that the structural and functional normalization of the tumor vasculature by the pretreatment with PE-SU5416 enabled liposomes to reach the deeper regions within tumor tissues, leading to more potent antitumor activity of PL-PTX.

DOI： 10.1021/mp300318q

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER/PLENUM PUBLISHERS  

Recombinant osteoprotegerin (OPG) has been proven to be useful for treating various bone disorders such as osteoporosis. To improve its in vivo pharmacological effect, OPG was conjugated to novel comb-shaped co-polymers of polyethylene glycol (PEG) allylmethylether and maleamic acid (poly(PEG), 5 kDa). Biodistribution and bioactivity were evaluated.
OPG was conjugated via lysine to poly(PEG) and to linear PEG (0.5 kDa and 5 kDa). Poly(PEG)-OPG was compared with linear PEG0.5k-OPG and PEG5k-OPG in terms of in vitro and in vivo efficacy and bone distribution.
The in vitro receptor binding study showed that poly(PEG)-OPG could be the most bioactive among the three PEG-OPG derivatives. Pharmacokinetic studies in ovariectomized (OVX) rats showed that serum half-life and AUC of poly(PEG)-OPG were comparable with those of linear PEG-OPG derivatives. For in vivo pharmacological effect, poly(PEG)-OPG showed the strongest inhibitory effect on bone resorption activity in OVX rats. Poly(PEG)-OPG demonstrated enhanced bone marrow distribution with higher selectivity than linear PEG5k-OPG.
Poly(PEG) modification could provide longer residence time in serum and higher bone-marrow specific delivery of OPG, leading to a higher in vivo pharmacological effect.

DOI： 10.1007/s11095-012-0807-4

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

To develop potent paclitaxel (PTX) formulations for cancer chemotherapy, we formulated PTX into polymeric nanoparticles composed of polyethylene glycol (PEG) and polylactic acid (PLA) block copolymer (PN-PTX). First, the physicochemical properties of PN-PTX prepared were assessed; the mean particle size was around 80nm and the zeta potential was found to be almost neutral. Next, the in vitro PTX release property was assessed by a dialysis method. Although rapid release of PTX was observed just after dosing, around 70% of PTX was stably incorporated in polymeric nanoparticles for a long time in the presence of serum. Then, the in vivo pharmacokinetics of PN-PTX after intravenous administration was investigated in Colon-26 (C26) tumor-bearing mice. Both polymeric nanoparticles and PTX incorporated exhibited a long blood circulating property, leading to enhanced permeability and retention (EPR) effect-driven, time-dependent tumor disposition of PTX. Tumor distribution increased gradually for 24h, and tissue uptake clearance of polymeric nanoparticles in the liver and spleen was lower than that of PEG liposomes. Since these results indicated that the in vivo disposition characteristics of PN-PTX were very favorable, we then evaluated the anti-tumor effect of PN-PTX in C26 tumor-bearing mice. However, PN-PTX did not exhibit any significant anti-tumor effect, presumably due to the poor PTX release from polymeric nanoparticles. From these results, it is considered that the favorable pharmacokinetic properties of nanoparticles and the drug incorporated do not always lead to its potent in vivo pharmacological activity, suggesting the importance of PTX release properties within tumor tissues.

DOI： 10.1248/bpb.b12-0020

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

To find out factors causing the low bioavailability of FX-93, a novel anticoagulant, its solubility, membrane permeability, and the effect of bile salt on the absorption of FX-93 were investigated. The solubility of FX-93 under physiological conditions ranged from 0.3 to 18.3 mg/mL and the dose number was calculated to be 0.020.27, suggesting that the intrinsic solubility of FX-93 should not be a limiting factor for oral absorption. Apparent permeability of FX-93 across Caco-2 cell monolayer suggested that its fraction of dose absorbed would range between 30% and 40% in humans. Furthermore, FX-93 was substantially absorbed from each segment of rat intestine. However, the decrease in the gastrointestinal transit rate significantly decreased maximum plasma concentration and area under the plasma concentrationtime curve of FX-93 after oral dosing in dogs, suggesting that FX-93 absorption would be suppressed by some components in the small intestinal lumen. An in situ rat administration study indicated that bile significantly decreased the intestinal absorption of FX-93 by two-thirds, which could be attributed to the decrease in FX-93 solubility by the interaction with bile or bile acid. Nuclear magnetic resonance spectroscopy analysis suggested that FX-93 would interact with bile salt between the naphthalene ring of FX-93 and steroidal backbone of bile salt. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:21342142, 2012

DOI： 10.1002/jps.23116

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Mucus on the nasal mucosa is translocated to the pharynx by ciliary beating, which is an important non-specific defense mechanism called mucociliary clearance (MC). MC is one of the important factors determining the rate and extent of drug absorption after nasal application. The purpose of this study is to evaluate MC using rat nasal septum under physiological condition in an in vitro system. The nasal septum was excised from rats anesthetized with urethane and the movement of fluorescent microspheres (FMS) applied on the nasal septum was observed with a fluorescence microscope. FMS were transported at a constant velocity in the same direction for a few minutes, but addition of 4% mucin solution on the nasal septum maintained MC for at least 90min after excision. With our evaluation system established by modifying the method of Saldiva, MC was determined to be around 1 mm/min. Furthermore, the ciliostatic effect of benzalkonium chloride was observed, and it was confirmed that beta-adrenergic antagonists and a cholinergic antagonist decreased MC, and that beta-adrenergic agonists and a cholinergic agonist tended to increase MC, indicating that our system is valid and useful for evaluating MC function and the effect of drugs and pharmaceutical additives for nasal application on MC.

DOI： 10.1248/bpb.35.889

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

The aim of this study was to investigate the feasibility of percutaneous absorption of CNS5161, a novel N-methyl-D-aspartate (NMDA) receptor antagonist developed as a potential treatment for neuropathic pain and other neurological disorders. Six pressure-sensitive adhesives (PSA) with different physicochemical properties, namely, styrene-isoprene-styrene (1) (SIS(1)), styrene-isoprene-styrene (2) (SIS(2)), silicone, acrylate with a hydroxyl group (acrylate(OH)), acrylate without a functional group (acrylate(none)) and acrylate with a carboxyl group (acrylate(COOH)), were investigated for their release of CNS5161 and its subsequent skin permeability. Among the adhesives examined, silicone PSA provided the highest value of transdermal flux of CNS5161, which could be attributable to the highest release rate from it due to its very high thermodynamic activity. Although CNS5161 was also in the supersaturated state in SIS(1) and SIS(2) PSAs, the release and transdermal permeation from these adhesives were slower than those from silicone PSA. As for the acrylic PSAs, the highest release rate and permeability of CNS5161 were observed for acrylate(OH) PSA, followed by acrylate(none) and acrylate(COOH) PSAs, but none of them was better in terms of either the release or the permeability of CNS5161 than silicone PSA. These results clearly indicated that silicone PSA would be the most suitable for transdermal delivery of CNS5161 and silicone PSA containing 10% CNS5161 would be suitable for clinical use in humans.

DOI： 10.1248/bpb.35.321

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-l-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity. Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.parint.2011.08.017

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

1. The pharmacokinetics of cilostazol was investigated after oral and intravenous administration in both male and female rats. After oral administration, area under serum concentration-time curve (AUC) was about 35-fold higher in female rats than in male rats, and absolute bioavailability was about 5.8-fold higher in female rats than in male rats.
2. Total body clearance (CL(total)) for female rats was around one-sixth of that for male rats. In vivo hepatic clearance (CL(h)) calculated based on isolated liver perfusion studies was even higher than or around 90% of the in vivo CL(total) of cilostazol for female and male rats, respectively, indicating that cilostazol is mainly eliminated by the liver in both male and female rats.
3. In vitro metabolism studies utilizing hepatic microsomes and recombinant cytochrome (CYP) isoforms clearly indicated that major metabolites of cilostazol were generated extensively with hepatic microsomes of male rats and that male-predominant CYP3A2 and male-specific CYP2C11 were mainly responsible for the hepatic metabolism of cilostazol. Therefore, the great sex differences in the pharmacokinetics of cilostazol were mainly attributed to the large difference in hepatic metabolism.
4. Our experimental results also suggested that the substantial metabolism of cilostazol in the small intestine and its possible saturation would be responsible for dose-dependent bioavailability in both male and female rats.

DOI： 10.3109/00498254.2011.590242

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Plasmodium falciparum, the major causative parasite for the disease, has acquired resistance to most of the antimalarial drugs used today, presenting an immediate need for new antimalarial drugs. Here, we report the in vitro and in vivo antimalarial activities of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against P. falciparum and Plasmodium berghei parasites. The N-251 showed high antimalarial potencies both in the in vitro and the in vivo tests (EC(50) 2.3 X 10(-8) M; ED(50) 15 mg/kg (per oral)). The potencies were similar to that of artemisinin in vitro and greater than artemisinin&apos;s activity in vivo (p.o.). In addition, N-251 has little toxicity: a single oral administration at 2000 mg/kg to a rat gave no health problems to it. Administration of N-251 to mice bearing 1% of parasitemia (per oral 68 mg/kg, 3 times a day for 3 consecutive days) resulted in a dramatic decrease in the parasitemia: all the 5 mice given N-251 were cured without any recurrence, with no diarrhea or weight loss occurring in the 60 days of experiment. N-251 deserves more extensive clinical evaluation, desirably including future trials in the human. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.parint.2011.04.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC APPLIED PHYSICS  

The aim of this research is to realize a small continuous flow system with emulsification devices. This system is designed for the generation of sub-micron or nano monodisperse emulsions. In this study, we have designed, fabricated, and evaluated a device that consists of a microchannel plate and an ultrasonic vibrating plate. This device can realize a continuous flow system and the plates are easily stacked. The oscillation frequency was 2.25 MHz. We succeeded in generating emulsions that have a diameter of 200 nm. We also designed the cross-sectional pattern of the microchannel of the ultrasonic device to increase residence time effectively. As a result, we have succeeded in obtaining emulsions that have a diameter of 80 nm. (C) 2011 The Japan Society of Applied Physics

DOI： 10.1143/JJAP.50.07HE24

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To find out potent paclitaxel (PTX) formulations for cancer chemotherapy, we formulated PTX in O/W emulsion and liposome selected as candidates of nanocarriers for PTX. Surface modification of these nanoparticles with polyethylene glycol (PEG) improved their in vivo behavior, but the effect of PEGylation on the pharmacokinetics of emulsion was not so remarkable and the release of PTX from emulsion was found to be very fast in blood circulation, indicating that emulsion would not be an adequate formulation for PTX. On the other hand, AUC of PEG liposome was 3.6 times higher than that of naked liposome after intravenous injection into normal rats due to the lower disposition into the reticuloendothelial system tissues such as liver and spleen. Since PEG liposome was able to stably encapsulate PTX in blood. AUC of PTX was also extensively enhanced after intravenous dosing of PTX-PEG liposome into normal rats. In the in vivo studies utilizing Colon-26 solid tumor-bearing mice, it was confirmed that FIX-PEG liposome delivered significantly larger amount of PTX to tumor tissue and provided more excellent anti-tumor effect than PTX-naked liposome. These results suggest that PEG liposome would serve as a potent PTX delivery vehicle for the future cancer chemotherapy. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2011.04.008

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Language：Japanese   Publisher：日本DDS学会  

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japan Society of Applied Physics  

In this study, a device using an ultrasonic vibration and a microchannel has been developed to obtain emulsions. The process of generating emulsions involves a Y-type microchannel and an ultrasonic device. Once micron-sized emulsions were generated by the Y-type microchannel, the micron-sized emulsions were sonicated using ultrasonic vibration to produce emulsions. Although the diameter of emulsions was 30 μm using the Y-type microchannel, the diameter of the sonicated emulsions was about 200 nm. In addition, as the applied voltage was increased, sonicated emulsions became smaller and the distribution became sharper.

DOI： 10.1143/JJAP.49.07HE13

CiNii Article

CiNii Books

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Language：Japanese  

CiNii Article

CiNii Books

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Authorship：Corresponding author  

CiNii Article

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Language：Japanese   Publisher：日本DDS学会  

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DOI： 10.1016/j.jconrel.2008.09.008

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CiNii Article

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DOI： 10.1007/s11095-008-9703-3

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Authorship：Corresponding author  

DOI： 10.1016/j.ijpharm.2008.09.050

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DOI： 10.1016/j.ijpharm.2008.09.027

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The relationship of gastric motor activity and gastric emptying of 0.7 mm caffeine pellets with their absorption was investigated in the fed state in healthy human subjects by simultaneous monitoring of antral motility and plasma concentrations. A kinetic model for gastric emptying-dependent absorption yielded multiple phases of gastric emptying and rate constants (kg) with large inter-individual differences and large variability in onset of gastric emptying (50-175 min). The model suggests that 50% of the dose is emptied in 1-2 h and over 90% emptied by 3.5 h following dosing, in all subjects. The maximum values of k(g) (k(g)(max)) were much greater than those reported for emptying of liquids in the fasted state and were comparable to kg values in the late Phase II/III of the migrating motor complex (MMC). The model described the observed irregular absorption rate-tithe and plasma concentration-time profiles adequately but not in detail. The model was more successful at simulating double-peak phenomena in absorption rate profiles and onset of caffeine absorption. The results suggest that gastric emptying regulates drug absorption of small particles in the fed state. Further, estimates of k(a) derived using the time-dependent absorption model were closer to the intrinsic absorption rate constant for caffeine. (C) 2008 Published by Elsevier B.V.

DOI： 10.1016/j.ejpb.2008.02.022

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 mu m) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2008.05.013

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The objective of this study is to evaluate the biodistribution characteristics of liposomes surface-modified with the mixture of polyethylene glycol (PEG) and polyvinyl alcohol (PVA) as a drug carrier for passive targeting of drugs. The liposomes (egg phosphatidylcholine:cholesterol=55:40, molar ratio) modified with both PEG and PVA (4:1 molar ratio) (PEG4%/PVA1% liposome) provided the largest AUC, which could be attributed to the smallest hepatic clearance of the liposomes. The liver perfusion studies clearly indicated that lower hepatic disposition of PEG4%/PVA1% liposome was ascribed to the decrease in its hepatic uptake via receptor-mediated endocytosis. Furthermore, the amounts of whole serum proteins and of opsonins such as complement C3 and immunoglobulin G adsorbed on PEG4%/PVA7% liposome were significantly smaller than those on the liposome solely modified with PEG (PEG5% liposome). On the other hand, several proteins were adsorbed at larger amount on PEG4%/PVA1 % liposome than PEG5% liposome, and the protein identification by LC-MS/MS suggested that some of those proteins including albumin might function as dysopsonins. The decrease in the adsorbed amount of several opsonins and the increase in the adsorbed dysopsonins would be responsible for its lower affinity to the liver and long residence in the systemic circulation of PEG4%/PVA1% liposome. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2008.04.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To elucidate the determinants of the in vivo anti-tumor efficacy of polyethylene glycol (PEG)-modified liposomal doxorubicin (DOX), we examined its anti-tumor effect against three different tumor cell lines (Lewis lung cancer (LLC), Colon-26 (C26) and B16BL6 melanoma (1316)) in vitro and in vivo. In vitro, LLC was the most sensitive tumor to DOX and liposomal DOX based on the MTT assay. However, the strongest in vivo anti-tumor effect was observed in the C26 tumor-bearing mice. The in vivo accumulation of radio-labelled PEG liposome in the C26 tumor after intravenous injection was significantly larger than in other tumors. The extent of vascularity assessed by immunohistochemical staining of CD31 was not directly related with the tumor accumulation of PEG liposome. On the other hand, Evans blue extravasation and secretion of VEGF in C26 tumors were higher than in LLC tumors, clearly demonstrating that the vasculature permeability was higher within C26 tumors. These results indicated that the vascular permeability within the tumor substantially affects the tumor accumulation of PEG liposome and may be one of the important determinants in the in vivo anti-tumor efficacy of PEG liposomal DOX. (C) 2008 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2008.03.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Purpose Firstly, to assess the effect of percutaneous endoscopic gastrostomy (PEG) tube placement on gastric emptying, gastrointestinal (GO tract motility and the rate of gastroesophageal reflux (GER). Secondly, to confirm whether correlations exist between drug absorption behaviour and GI tract motility using the combination method of absorption function analysis with the motility study.
Methods Subjects comprised 11 patients with neurological dysphagia. Gastric-emptying scintigraphy was performed both before PEG via nasogastric tube feeding and after PEG placement. After fasting for more than 8 h, each patient was administered 111 MBq of Tc-99m-labelled diethylenetriaminepentaacetic acid (DTPA) with a 100 ml liquid meal via a nutrition tube. Dynamic imaging was performed immediately after administration of a radiolabelled liquid meal for a 1 h period and static imaging was performed after 1, 2, 3 and 6 h. Gastric emptying half-time (T-50) was calculated in each patient, and GER ratio and GI transit rate were also evaluated. Simultaneously, we administered 10 mg of famotidine in six of the 11 patients and measured serum concentrations of famotidine at 0, 1, 2, 3 and 6 h. Using the time-concentration curve of famotidine, the maximum concentration of famotidine (C-max) and area under the curve of famotidine (AUC(f)) were calculated for each patient.
Results In seven of 11 patients, T-50 changed after PEG placement, but not significantly. The GER ratio was significantly decreased and complicated pneumonia improved after PEG placement. GI transit rate for each GI segment was unchanged after PEG placement. Significant linear correlations were identified between T-50 and both C-max and AUC(f).
Conclusion Gastric-emptying scintigraphy with Tc-99m-DTPA was effective in the evaluation of GI transit before and after PEG, as well as in assessing GER. Motility and famotidine absorption were maintained after PEG placement. Significant linear correlations were found between T-50 and both Cmax and AUC(f). These findings suggest that drug absorption may have some relationship between T-50. The result may be more reliable with a larger population.

DOI： 10.1097/MNM.0b013e3282f64568

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To evaluate the effect of coupling of recombinant human serum albumin (rHSA) onto the surface of poly(ethylene glycol)-modified liposorne (PEG liposome) on the in vivo disposition characteristics of liposomal doxorubicin (DXR), the pharmacokinetics and tissue distribution of DXR were evaluated after intravenous administration of rHSA-modified PEG (rHSA/PEG) liposomal DXR into tumor-bearing rats. rHSA/PEG liposome prepared using a hetero-bifunctional cross-linker, N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP), efficiently encapsulated DXR (over 95%). rHSA/PEG liposomal DXR showed longer blood-circulating property than PEG liposornal DXR and the hepatic and splenic clearances of rHSA/PEG liposornal DXR were significantly smaller than those of PEG liposomal DXR. It was also demonstrated that the disposition of DXR to the heart, one of the organs for DXR-related side-effects, was significantly smaller than free DXR. Furthermore, the tumor accumulation of rHSA/PEG liposomal DXR was significantly larger than that of PEG liposomal DXR. The "therapeutic index", a criterion for therapeutic outcome, for rHSA/PEG fiposornal DXR was significantly higher than PEG liposomal DXR. These results clearly indicate that rHSA-conjugation onto the surface of PEG liposome would be a useful approach to increase the effectiveness and safety of PEG liposomal DXR. (c) 2007 Elsevier BX All rights reserved.

DOI： 10.1016/j.ijphartn.2007.11.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER/PLENUM PUBLISHERS  

Purpose. Mechanism for double-peak occurrence in plasma concentration profile after oral administration of drugs is controversial, although irregular gastric emptying would be an important factor. The objective of this study was to assess the effect of gastric emptying and a weight function, i.e. pharmacokinetics after reaching the systemic circulation, on the double-peak appearance in plasma concentration profiles.
Materials and Methods. Alprazolam, which generates irregular gastric emptying, was orally co-administered with theophylline to rats, and the plasma concentration profiles or absorption rates were compared between the two drugs. Both drugs are highly absorbable, but alprazolam is rapidly eliminated from plasma, while the elimination of theophylline is very slow.
Results. Oral administration of alprazolam generated the irregular gastric emptying profiles, resulting in multiple peaks in the absorption rate profiles of both drugs. The double peaks in the absorption rate profiles led to the double peaks in plasma concentration profiles for alprazolam, but not necessarily for theophylline. Simulation study clearly indicated that the slower elimination from plasma made the first peak less recognizable.
Conclusions. The irregular gastric emptying could be a main reason for the double peaks in plasma concentration profiles. However, the frequency of double-peak occurrence depends on the weight function, particularly the elimination rate, of each drug.

DOI： 10.1007/s11095-007-9469-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Mean plasma concentration-time profile of griseofulvin, a BCS class II drug, orally administered as powders into rats, was predicted based on GITA model. However, it was very difficult to predict the individual plasma profile because of large inter-individual difference. As the absorption of griseofulvin would be rate-limited by the dissolution process, we tried to analyze the in vivo dissolution kinetics of griseofulvin by focusing on gastric emptying and intestinal transit as physiological factors influencing the in vivo dissolution kinetics. After oral administration of griseofulvin, theophylline and sulfasalazine into rats, gastric emptying and intestinal transit were simultaneously estimated by analyzing the absorption kinetics of theophylline and observing the appearance of sulfapyridine in plasma, respectively. Gastric emptying kinetics was not significantly correlated with absorption or dissolution behavior of griseofulvin. On the other hand, the cecum-arriving time reflecting the intestinal transit was significantly correlated with both AUC and total dissolved amount of griseofulvin. T-max of griseofulvin also increased with the increase of cecum-arriving time. These results clearly indicate that the longer residence time could lead to the higher dissolution and absorption of griseofulvin and that the variance of intestinal transit could be responsible for the inter-individual difference of the in vivo absorption behavior. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2007.10.008

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Language：English   Publisher：Japanese Society of Pharmaceutical Health Care and Sciences  

Lung transplantation has proved to be an effective treatment worldwide for a variety of end-stage lung diseases. In Japan, living-donor lung transplantation is the predominant procedure used. In this and other types of transplantation, the calcineurin inhibitor cyclosporine (CYA) is frequently used as an immunosuppressive drug. However, this drug requires strict control of dosing to minimize the risk of rejection and over-imrnunosuppression, and for the orally administered drug, interand intra-individual bioavailability vary widely. Intensive drug monitoring is therefore necessary. In this study, 25 patients who received lung allografts from living donors between October 1998 and January 2006 at Okayama University Hospital were investigated to see if there was any correlation between the CYA concentration-dose ratio and biochemical parameters. The most significant correlation was between the CYA concentration-dose ratio and total cholesterol, with a correlation coefficient of 0.46. As for individual results in this respect, 14 of 25 patients had a correlation coefficient of 0.5 or greater, and the highest was 0.92. There was thus a definite correlation between the CYA concentration-dose ratio and total cholesterol in patients who had undergone living-donor lung transplantation.

DOI： 10.5649/jjphcs.34.381

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Other Link： https://jlc.jst.go.jp/DN/JALC/00312734549?from=CiNii

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The relationship between the time-dependent change in serum proteins adsorbed on nanoparticles and their disposition to the liver was investigated by employing lecithin-coated polystyrene nanosphere with a size of 50 nm (LNS-50) as a model nanoparticle in rats. The total amount of proteins adsorbed on LNS-50 increased and the qualitative profile of serum proteins adsorbed on LNS-50 changed during the incubation with serum up to 360 min. The liver perfusion study indicated that the hepatic uptake of LNS-50 incubated with serum for 360 min was significantly larger than those of LNS-50 incubated for shorter period. It was suggested that the increase in the hepatic uptake of LNS-50 with the increase in incubation time would be ascribed mainly to the increase in the opsonin-mediated uptake by Kupffer cells. Semi-quantification of major opsonins, complement C3 (C3) and immunoglobulin G (IgG), and in vitro uptake study in primary cultured Kupffer cells demonstrated that the increase in C3 and IgG amounts adsorbed on LNS-50 was directly reflected in the increased disposition of LNS-50 to Kupffer cells. These results indicate that the amounts of opsonins associated on nanoparticles would change over time and this process would be substantially reflected in the alteration of their hepatic disposition characteristics. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2007.04.036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The in-vivo absorbability of drugs categorized into the biopharmaceutics classification system (BCS) class II is very difficult to be predicted because of the large variability in the absorption and/or dissolution kinetics and the lack of an adequate in-vitro system for evaluating the dissolution behavior. We tried to predict the in-vivo absorption kinetics of griseofulvin, categorized into BCS class II, orally administrated as powders into rats, based on Gastrointestinal-Transit-Absorption model (GITA model), consisting of the absorption, dissolution and GI-transit processes. Using the dissolution rate constants (k(dis)) of griseofulvin obtained with JP I st solution, JP 2nd solution, FaSSIF, FeSSIF and modified SIBLM as a medium, simulation lines were not able to describe the observed mean plasma profile at all. On the other hand, a calculated line provided by employing k(dis) obtained with MREVID 2 (medium reflecting in-vivo dissolution 2), a new medium, was in better agreement with the observed mean plasma profile than existing media, indicating that the utilization of adequate k(dis) value made it possible to predict the in-vivo absorption kinetics of drugs classified into BCS class II based on GITA model and that MREVID 2 could be a useful medium for describing the in-vivo dissolution kinetics. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2007.03.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To evaluate the effect of coupling of albumin onto the surface of poly(ethylene glycol)-modified liposome (PEG liposome) on the in vivo disposition of liposome, pharmacokinetics and tissue distribution were examined after intravenous administration of rat serum albumin-modified PEG (RSA[PEG) liposome into rats. RSA/PEG liposome showed longer blood-circulating property than PEG liposome and the hepatic clearance for RSA/PEG liposome was significantly smaller than that for PEG liposome. Single-pass liver perfusion experiments also showed that the hepatic disposition of RSA/PEG liposome was much less than that of PEG liposome and that pre-treatment of liver with trypsin did not significantly reduce the hepatic disposition of RSA/PEG liposome, suggesting that RSA/PEG liposome could avoid the hepatic uptake via the receptor-mediated endocytosis. To unravel the mechanism behind the less affinity of RSA/PEG liposome to the liver, serum proteins associated on their surface were quantitatively and qualitatively assessed. The results showed that the coupling of albumin onto PEG liposome significantly reduced the total amount of serum proteins associated onto the surface, and SDS-PAGE revealed that the decrease in the association with liposomes for several serum proteins, which might have opsonic activity. From these findings, introduction of serum albumin onto PEG liposome could be useful to develop a new nanoparticulate formulation with a better pharmacokinetic property. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2006.08.026

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The sustained-release (SR) adhesive microspheres successfully improved the absorption of furosemide, of which the absorption is limited to the upper small intestine, after oral administration to humans based on the adhesion to the gastric mucosa in our previous study. To develop a new drug using SR-adhesive microspheres, however, some adequate animal models should be needed to predict the potency of the formulation in humans. To find out an adequate animal model, the effect of the SR-adhesive microspheres on furosemide absorption was investigated in rats, dogs and monkeys and the release kinetics of furosemide from SR-adhesive microspheres was also studied. SR-adhesive and SR-non-adhesive microspheres showed very similar characteristics of drug release. The rotation speed did not affect the release kinetics, but higher pH increased the drug release from both microspheres. The absorption of furosemide after SR-adhesive microspheres administration to rats and dogs was significantly higher than that after SR-non-adhesive microspheres administration, which was very similar to the results obtained in humans. On the other hand, in monkeys, SR-adhesive microspheres were not able to improve the absorption of furosemide at all. These findings indicated that rats and dogs were in vivo animal models suitable for predicting the potency of SR-adhesive microspheres in humans. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2006.09.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We tried to evaluate the possible involvement of fetuin in the scavenger receptors (SRs)-mediated hepatic uptake of polystyrene nanospheres with the size of 50 mn (NS-50), which has surface negative charge (zeta potential = -21.8 +/- 2.3 mV). The liver perfusion studies in rats revealed that the hepatic uptake of NS-50 pre-coated with fetuin (NS-50-fetuin) was significantly inhibited by poly mosinic acid (poly 1), a typical inhibitor of SRs, whereas that of plain NS-50 or NS-50 pre-coated with BSA (NS-50-BSA) was not. The uptake of NS-50-fetuin by cultured Kupffer cells was also significantly inhibited by poly 1, and anti-class A scavenger receptors (SR-A) antibody, suggesting that fetuin on NS-50 mediated the recognition and internalization of NS-50 by Kupffer cells and at least SR-A would be responsible for the uptake. Taken that Western blot analysis confirmed that fetuin certainly adsorbed on the surface of NS-50 after the incubation of NS-50 with serum, the results obtained in the present study indicate that fetuin would be one of the serum proteins that were substantially involved in the hepatic uptake of NS-50 via SRs. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2006.08.025

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Authorship：Lead author   Language：Japanese   Publisher：PHARMACEUTICAL SOC JAPAN  

The development of combinatorial chemistry and high-throughput screening techniques has made it possible to generate many new drug candidates very rapidly, but it has also resulted in a number of poorly soluble and/or poorly absorbable candidates. A new trend in drug development based on pharmacogenomics or the development of molecular-targeted drugs is also spurring the tendency, and it does not necessarily lead to good output in terms of the development of new drugs. it is attractive to improve membrane permeability as well as solubility by using adjuvants, because this method could be applicable for various drugs. However, the practical use of absorption-enhancing adjuvants has been limited because of the potential local toxicity. Therefore suppressing the potential local toxicity would lead to the successful development of safe preparations with improved absorption using adjuvants. Our biochemical and histopathologic studies showed that several amino acids such as taurine and L-glutamine had cytoprotective activity, and it has been found that the combinatorial use of sodium laurate (C12) with these amino acids could maintain the absorption-enhancing ability of C12. A suppository preparation containing C12 and taurine remarkably improved the rectal absorption of rebamipide, classified as BCS class IV, and the preparation was safe to the rectal mucosa. For the mechanisms of cytoprotective action by these amino acids, it has been found that they suppress the intracellular calcium level, induce the expression of heat-shock protein 70, and inhibit the release of histamine and apoptosis.

DOI： 10.1248/yakushi.127.589

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Language：English   Publisher：TAYLOR & FRANCIS INC  

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Language：English   Publisher：TAYLOR & FRANCIS INC  

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Language：English   Publisher：TAYLOR & FRANCIS INC  

DOI： 10.1016/j.ijpharm.2007.04.036

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Language：English   Publisher：TAYLOR & FRANCIS INC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The synergetic improving effect of bile acids with spermine (SPM), a major polyamine, on the absorption of rebamipide, a poorly soluble and poorly absorbable drug (BCS Class IV), was evaluated in rats and beagle dogs. Although the absorption of rebamipide was improved by the addition of polyamines alone in normal rats, it was not improved in bile duct ligated (BDL) rats. The combinatorial use of sodium taurocholate (STC), a bile acid, with SPM improved the absorption of rebamipide even in BDL rats. In the beagle dogs, the oral administration of SPM alone did not enhance the absorption of rebamipide, but the combinatorial use of STC with SPM improved the absorption as well as in the BDL rats. These results indicate that bile acids are indispensable for the novel formulation containing SPM to improve the absorption of rebannipide after oral administration. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2006.07.015

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

In our previous studies, taurine (Tau) and L-glutamine protected intestinal epithelial cells from local toxicity caused by sodium laurate (C12), an absorption enhancer, while maintaining sufficient absorption-enhancing effect of C12, and it was suggested that one of the mechanisms behind cytoprotection by amino acids was to prevent intracellular Ca2+ concentration ([Ca2+](i)) from increasing. In the present study, we focused on the elucidation of mechanisms by which C12 increases [Ca2+](i) and by which amino acids suppress [Ca2+](i) by utilizing Caco-2 cells. Removal of extracellular Ca2+ remarkably suppressed the increase of [Ca2+](i) by C12. Compound 48/80, an inhibitor of phospholipase C, and verapamil, a Ca2+ channel inhibitor, also significantly prevented [Ca2+](i) elevation. These results indicate that C12 augmented [Ca2+](i) due to (a) influx of extracellular Ca2+ through Ca2+ channel, (b) release of Ca2+ from the endoplasmic reticulum. Cytoprotective action by amino acids was significantly attenuated by orthovanadate, an inhibitor of plasma membrane Ca2+-ATPase (PMCA), suggesting that amino acids activate PMCA to enhance the efflux of intracellular Ca2+. Furthermore, Tau enhanced the mitochondrial uptake of Ca2+, which could contribute to the decrease in [Ca2+](i). These results clearly show that amino acids protect intestinal epithelial cells from being damaged by modulating intracellular Ca2+ dynamics. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/jps.20712

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

A novel sustained-release (SR) system, disintegration-con trolled matrix tablet (DCMT), was developed for poorly water-soluble drugs. DCMT, consisting of wax and solid dispersion (SD) granules containing a disintegrant, could control the release of nilvadipine (Nil)), a model compound, by its disintegration. In the present study, two DCMTs (DCMT-1 and DCMT-2) with different release rates of NO were orally administered to beagle dogs, and in vivo absorption of NiD from DCMTs was compared with that from immediate-release (IR) tablets. DCMTs successfully sustained the absorption of NiD longer than IR tablets, while they did not decrease the bioavailability of NiD. DCMT-2, providing the slower release of NiD than DCMT-1, prolonged the absorption longer than DCMT-1. In vivo absorption profiles of NO from DCMTs were significantly correlated with in vitro release profiles, suggesting that the release property from DCMTs would maintain regardless of the change in physiological condition through the gastrointestinal tract. Furthermore, the food intake did not affect the absorption of NO after oral administration of DCMT-2. The present results strongly indicate that the DCMT system would be a promising SR system, which could improve the solubility and sustain the absorption of poorly water-soluble drugs. (c) 2006 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2006.01.020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

In order to develop a novel oral formulation that can safely improve the intestinal absorption of poorly absorbable drugs, polyamines such as spermine (SPM) and spermidine (SPD) was examined as an absorption enhancing adjuvant in rats. The absorption of rebamipide, classified into BCS Class IV, from colon was significantly improved by SPM or SPD, and the enhancing ability of SPM was larger than that of SPD. As a possible mixing and/or interaction of polyamines with bile acids were expected, the combinatorial use of sodium taurocholate (STC) with polyamines was also examined. The absorption of rebamipide was drastically improved by the combinatorial use of SPM or SPD with STC. As STC itself did not enhance the absorption of rebamipide so much, it was considered that polyamines and STC had a synergistic enhancing effect. In-vivo oral absorption study was also performed to investigate the effectiveness and safety of polyamines and their combinatorial use with STC in rats. Although the enhancing effect slightly attenuated comparing with the in-situ loop study, the absorption of rebamipide was significantly improved and the combinatorial use of 10 mM SPM with 25 mM STC showed the largest enhancing effect. Histopathological studies clearly showed that any significant change in stomach and duodenum was not caused by SPM (10 mM), SPD (10 mM) or their combinatorial use with STC (25 mM) at 1.5 or 8.0 h after oral administration. Taken all together, polyamines, especially SPM, and its combinatorial use with STC could improve the absorption of poorly absorbable drugs without any significant changes in gastrointestinal tract after oral administration in rats. (c) 2005 Elsevier B.V All rights reserved.

DOI： 10.1016/j.jcornel.2005.11.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The purpose of the present study was to investigate the effects of particle size on the dissolution and oral absorption of cilostazol. Three types of suspensions having different particle size distributions were prepared of the hammer-milled, the jet-milled cilostazol crystals and the NanoCrystal (R) spray-dried powder of cilostazol. In vitro dissolution rate of cilostazol was significantly increased by reducing the particle size. The dissolution curves of the cilostazol suspensions were in good agreement with the simulation based on the Noyes-Whitney equation. The bioavailability of cilostazol after oral administration to dogs was increased with reducing the particle size. While positive food effect on the absorption was observed for the suspensions made of the hammer-milled and the jet-milled crystals, no significant food effect was found for the suspension made of the NanoCrystal (R) cilostazol spray-dried powder. These results could be qualitatively predicted from the in vitro dissolution data using the bio-relevant media, FaSSIF and FeSSIF. In conclusion, the NanoCrystal (R) technology is found to be efficient to improve the oral bioavailability of cilostazol and to avoid the food effect on the absorption. (c) 2005 Elsevier B.V All rights reserved.

DOI： 10.1016/j.jconrel.2005.11.013

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

We previously reported that the fatty base suppository containing sodium laurate (C12) and taurine (Tau) (C12-Tau suppository) could enhance the colonic absorption of rebamipide, a poorly water-soluble and poorly absorbable drug, without any serious mucosal damages in rats. In the preset study, in order to make C12-Tau suppositories available for practical use, the scaling-up studies of animal and formulation size were performed, compared with the suppositories containing sodium caprate (C10) (C10 suppository) at the same amounts as those contained in the commercial products. Twenty-mg C12 improved the dissolution of rebamipide from suppository remarkably and the addition of 30-mg Tau only slightly decreased the dissolution rate. The absorption of rebamipide from rabbit rectum was more markedly improved by suppositories containing C12 than C10 suppositories. Although Tau tended to attenuate the absorption-enhancing effect of C12, several C12-Tau suppositories kept high bioavailability values, which were much higher than control. Histopathological studies showed that Tau exerted the cytoprotective action and that C12-Tau suppositories were better than C10 suppositories in safety. Considering the balance between efficacy and safety, the suppository containing 10- or 20-mg C12 with 30-mg Tau is better than C10 suppositories as commercial products and could be promising for practical Use human.

DOI： 10.1248/bpb.29.330

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The goal of this study is to develop a novel sustained-release (SR) system for poorly water-soluble drugs by applying solid dispersion (SD) technique for improving the solubility. The developed SR system, disintegration-controlled matrix tablet (DCMT), consists of hydrogenated soybean oil (HSO) as wax and SD granules containing low-substituted hydroxypropylcellulose (L-HPC) as a disintegrant. In this study, nilvadipine (NiD) was chosen as a model compound. Sustained-release profiles of NiD from DCMT were identically controlled in several dissolution mediums in spite of varying pH and agitation speed. The release of NiD from DCMT was sustained more effectively by increasing the amount of wax or by decreasing the amount of disintegrant, and supersaturation of NiD was achieved without any re-crystallization in dissolution medium. The release rate of NiD from DCMT was controlled by the disintegration rate of tablet. The release profile of NiD was described by the Hixson-Crowell's model better than zero-order kinetics, first-order kinetics and Higuchi's model, which supports that the release of NiD from DCMT is regulated by the disintegration of the tablet. From this study, it was clarified that DCMT was one of the promising SR systems applying SD for the poorly water-soluble drugs. (c) 2005 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jcornel.2005.08.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Controlled-release morphine suppositories were prepared by utilizing polyglycerol ester of fatty acid (PGEF). The addition of PGEF to fatty suppository base Witepsol H15 resulted in a decrease of morphine release rate from suppositories. Among PGEFs examined, decaglycerol heptabehenate (HB750) was the most effective additive for the controlled-release of morphine from fatty suppositories. The apparent viscosity of suppository bases increased with the increase in HB750 content, and good correlation was observed between the apparent viscosity of suppository bases at 37 degrees C and the amount of HB750 added in the mixed base. The in vitro release rate of morphine was decreased by the addition of HB750 and the release rate constant (Higuchi's rate constant) for morphine release was significantly correlated with the HB750 content in the mixed bases as well as the apparent viscosity of mixed bases, indicating that the release of morphine from the mixed bases could be regulated by the HB750 content in the mixed bases. After rectal administration of Witepsol H-15-HB750 mixed suppositories to dogs, plasma concentrations of morphine did not increase rapidly at early time periods, but relatively high levels of morphine in plasma were sustained for longer time periods. Mean residence time of morphine was considerably prolonged without changing relative bioavailability in the case of the mixed base suppositories containing 15-17% HB750, compared with the Witepsol H15 suppository, clearly indicating that the mixed bases containing HB750 are expected to be useful for the design of controlled-release morphine suppositories.

DOI： 10.1248/bpb.28.1480

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

To investigate the role of serotonin (5-HT), an important neurotransmitter and hormone/paracrine agent in the small intestine, in the transport activity of P-glycoprotein (P-gp), the intestinal transport of quinidine, a P-gp substrate, was examined in 5-HT-depleted rats prepared by intraperitoneal administration of pchlorophenylalanine, a specific inhibitor of tryptophan hydroxylase in 5-HT biosynthesis. In the in vitro transport study, quinidine transport across rat jejunum was significantly enhanced in both the secretory and absorptive directions under 5-HT-depleted conditions, although the secretory transport was still predominant. The electrophysiological study suggested that the quinidine transport via passive diffusion was enhanced presumably through a paracellular route. This might be due to looser tight junctions under 5-HT-depleted conditions. The voltage-clamp technique clearly indicated that the secretory transport of quinidine through the transcellular pathway was also enhanced by the depletion of 5-HT. Furthermore, 5-HT depletion increased verapamil-sensitive secretory transport of quinidine in rat jejunum. These results indicate that the secretory transport of quinidine via P-gp was significantly enhanced under 5-HT-depleted conditions. The level of ATP, an energy source for functioning P-gp, wet weight of jejunum, and total protein level in rat jejunal mucosa were not changed by 5-HT depletion, but the expression of P-gp in the brush-border membrane of rat jejunum was significantly induced, which is partly responsible for the enhancement of P-gp activity under the 5-HT-depleted condition.

DOI： 10.1124/jpet.104.071290

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To develop the suitable film formulations of propranolol hydrochloride (PPL) containing enhancers for transdermal use, polymeric film formulations were prepared by employing ethyl cellulose (EC) and polyvinyl pyrrolidone (PVP) as a film former, and dibutyl phthalate (DBP) as a plasticizer. Terpenes such as menthol and cineole, and propylene glycol (PG) were also employed as a chemical enhancer to improve the skin penetration of PPL. The film preparations were characterized in physical properties such as uniformity of drug content, thickness and moisture uptake capacity. Release and skin permeation kinetics of PPL from film preparations were examined in the in vitro studies using a Franz-type diffusion cell. The uniformity of drug content was evidenced by the low S.D. values for each film preparation. The moisture uptake capacity and drug release rate increased with the increase of PVP in each preparation. Enhancers examined in the present study also increased the moisture uptake capacity and release rate of PPL from the film preparations. Increasing the concentration of PPL from 1 to 2 mg/cm(2) in the film enhanced the release rate of PPL, while no effect of enhancer concentrations on the release rate from the film preparations was observed. In vitro skin permeation study showed that cineole was the most promising enhancer among the enhancers examined in the present study and suggested that the suitable compositions of film preparation would be EC:PVP:PPL = 6:3:4 with 10% (w/w) cineole and 7:2:4 with 10% (w/w) PG and cineole, which provided high skin permeation rates at 93.81 +/- 11.56 and 54.51 +/- 0.52 mug/cm(2)/h, respectively. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2004.11.007

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The purpose of this work was to investigate the effect of blood flow in the skin on the direct penetration of topically applied drugs into the muscular layer, and to show that the skin blood flow could also be one of the important factors determining the direct penetration of drugs to the muscular layer. In vivo percutaneous absorption study was performed for antipyrine, salicylic acid or diclofenac by using rats with tape-stripped skin. Phenylephrine, which is well known to reduce the local blood flow by vasoconstrictor action, was topically applied to decrease the local blood flow in the skin. The concentrations of drugs in viable skin and muscle, and the local blood flow in the skin under the applied and the contralateral sites were determined to evaluate the effect of the local blood flow on the delivery of topically applied drugs into the muscular layer. Dose dependency for the effect of phenylephrine was, first of all, investigated for antipyrine in the range from 0.4 to 10 mumol. The distribution of antipyrine into the viable skin and muscular layer 2 h after topical application significantly increased, but the effect of phenylephrine was saturated around 2 mumol and the dose-dependent profiles for both tissues were almost superimposed. On the other hand, the fraction dose absorbed, plasma concentration and concentrations in viable skin and muscular layer under the contralateral site showed the decreasing tendency and the saturation of the effect around 2 mumol. To confirm the effect of phenylephrine on the local blood flow in the skin, the skin blood flow was measured 2 h after topical application of 2 mumoI phenylephrine, and the significant decrease in the blood flow was recognized. In vivo percutaneous absorption studies were performed for salicylic acid and diclofenac, too. Extensive enhancement of penetration into the viable skin and muscular layer was observed for both drugs, although total absorption from the donor cell showed the decreasing tendency. In conclusion, direct penetration of drugs applied topically is enhanced by reducing the local blood flow in the skin, which would be a possible approach to improve the local delivery of drugs applied topically. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2004.09.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

We evaluated the in vivo disposition characteristics of polystyrene nanospheres (NS) with the particle size of 50 nm (NS-50) pre-coated with human serum albumin (HSA) after intravenous administration in rats. HSA-coated NS-50 showed much longer blood-circulating property and the hepatic uptake clearance for HSA-coated NS-50 was about 115 of that for NS-50. In parallel with the results obtained in the in vivo study, liver perfusion experiments also showed that the hepatic disposition of HSA-coated NS-50 was much less than that of NS-50 in the presence of serum in the perfusate. To unravel the mechanism behind the less affinity of HSA-coated NS-50 to the liver, serum proteins associated on the surface was quantitatively and qualitatively assessed. The results indicated that pre-coated HSA impaired subsequent association of serum proteins onto the surface, suggesting that the association of a given serum protein with opsonic activity might be suppressed by HSA pre-coating. From these findings, pre-coating of nanoparticles with serum albumin could be useful to prevent their rapid clearance by mononuclear phagocyte system in vivo. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2004.07.028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To develop the safe formulation that can safely improve bioavailability of poorly absorbable drugs and that is practically available, we prepared the suppositories of rebamipide, a poorly soluble and poorly absorbable antiulcer drug, by employing the combinatorial use of sodium laurate (C12), an absorption enhancer, with taurine (Tau) or L-glutamine (L-Gln), an adjuvant exerting the cytoprotective action. Although the dissolution of rebamipide from fatty base (FB) suppository prepared using Witepsol H-15 was very slow, it was remarkably improved by the addition of C12 and L-Gin or Tau into the suppository. On the other hand, the dissolution of rebamipide from water-soluble base (WB) suppository prepared using polyethylene glycol was very rapid and the addition of adjuvants did not influence its dissolution so much. Rectal absorption of rebamipide examined in rats was remarkably improved by FB suppository containing C12 or both Cl 2 and Tau, while the enhancing effect of C12 was relatively small in the case of WB suppositories. Biochemical and histopathological studies have confirmed that FB suppository containing both C12 and Tau or L-Gln did not cause any serious local damage, while FB suppository containing C12 only caused the erosion and shrinkage for a lot of rectal epithelial cells. In conclusion, FB suppository employing the combinatorial use of C12 with Tau could be a promising formulation that is effective and safe enough for poorly absorbable drugs to be practically administered. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2004.06.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To prepare the sustained release suppositories, solid fats such as polyglycerol ester of fatty acids (PGEFs) or beeswax were utilized with a fatty suppository base, Witepsol H15. PGEFs such as decaglycerol heptabehenate (HB750) and hexaglycerol pentastearate (PS500). and beeswax have relatively high melting points. The addition of PGEFs or beeswax to Witepsol H15 increased the apparent viscosity of suppository bases at 37 degreesC without any large change in the melting point of Witepsol H15. Moreover, the apparent viscosity of a mixed base with HB750, PS500 or beeswax at 37 degreesC was significantly correlated with the amount of each solid fat in a mixed base. The release of acetaminophen (AAP), a model drug, from suppositories was delayed by HB750, PS500 or beeswax, and an excellent correlation was observed between the apparent viscosity of these mixed bases and Higuchi's rate constants in each mixed base suppository, suggesting that these solid fats could regulate the drug release from the mixed base suppositories by changing their viscosity. In the in vivo absorption study in rats, several suppositories made from Witepsol H15-HB750 or Witepsol H15-beeswax mixed bases prolonged the rectal absorption of AAP without reducing AUC. In conclusion, by using solid fats such as HB750 and beeswax with relatively high melting points, it is possible to control the rate of drug release from fatty base suppositories for maintaining the plasma concentration of drugs for longer time periods. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2004.03.030

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

1. To elucidate the mechanisms involved in the sinusoidal efflux of sulfate and glucuronide metabolites of 4-methylumbelliferone (4MU), isolated rat liver perfusion studies were performed under several conditions.
2. The effect of sodium azide on the hepatic handling of both conjugates was examined. The net sinusoidal efflux clearance (CL eff ) based on the unbound concentration in the liver did not change for 4MU glucuronide (4MUG) or significantly increase for 4MU sulfate (4MUS), suggesting that the sinusoidal efflux of both conjugates is not mediated by the transport systems dependent on adenosine triphosphate.
3. Under Cl - -depleted conditions, the CL eff of 4MUG significantly decreased, but the saturation of its sinusoidal efflux rather than the transport system dependent on Cl - might be involved because the hepatic concentration of 4MUG was extensively higher than that of the control study due to the extremely attenuated biliary excretion. The CL eff of 4MUS also significantly decreased, but its hepatic concentration was not different from that in the control study, suggesting that the transport system using Cl - is involved in the sinusoidal efflux of 4MUS.
4. The effect of glutathione was examined. CL eff of 4MUG was not affected by the additional glutathione, but CL eff of 4MUS decreased significantly, suggesting that some transport system sensitive to glutathione is involved in the sinusoidal efflux of 4MUS, but not of 4MUG.
5. Transporters such as Oatp1, Oatp2 and/or Npt1 might be involved in the sinusoidal efflux of 4MUS, but 4MUG is secreted from the sinusoidal membrane via the systems that are totally different from those for 4MUS.

DOI： 10.1080/00498250410001691262

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The mechanisms involved in the hepatic uptake of negatively charged carboxylated-polystyrene nanospheres with a size of 50 nm (CNS-50) were examined in rats. The liver perfusion experiments revealed that hepatic disposition of CNS-50 in the absence of serum could be partially ascribed to the direct recognition of the surface negative charge by scavenger receptors. On the other hand, the apparent negative charge of CNS-50 surface dramatically reduced in the presence of serum, because the adsorption of serum protein on their surface results in masking their intrinsic negative charge. However, hepatic disposition of CNS-50 in the presence of serum was significantly inhibited by poly inosinic acid (poly I), a typical inhibitor for scavenger receptors, and the extent of inhibition by poly I was even larger than that in the absence of serum, suggesting that the serum proteins associated on CNS-50 surface could be recognized by scavenger receptors. These results indicate that not only the intrinsic negative charge but also serum proteins associated on the surface play an important role in hepatic uptake of negatively charged particles via scavenger receptors. (C) 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2004.03.004

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Authorship：Lead author   Language：English  

DOI： 10.2133/dmpk.19.198

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The aim of this study was to establish a new preparation method for solid dispersion formulation (SDF) of tacrolimus, a poorly water-soluble drug, without dichloromethane, because no use of dichloromethane is recommended by ICH harmonized tripartite guideline. To select the appropriate carrier, three different SDFs with polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) were prepared by the conventional solvent method, in which tacrolimus and the carrier were completely dissolved in the mixture of dichloromethane and ethanol. Powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) patterns indicated that tacrolimus exists in an amorphous state in all three SDFs. The supersaturated dissolution profiles of tacrolimus were observed in all SDFs, and the highest level of supersaturation for tacrolimus was obtained and maintained for 24 h from SDF with HPMC. On the other hand, the supersaturated level from SDF with PEG 6000 or PVP decreased rapidly. The in vivo oral absorption study in dogs showed that bioavailability of tacrolimus from SDF with HPMC was remarkably improved compared with the crystalline powder. It was clarified that HPMC is the most appropriate carrier for SDF of tacrolimus. Then, SDF of tacrolimus was prepared by the new method, which allows us to make SDF of tacrolimus by swelling HPMC with ethanol, in which tacrolimus was completely dissolved. This new method does not need dichloromethane. The physicochemical properties of SDF with HPMC prepared by the new method were the same as those of SDF prepared by the conventional solvent method. Furthermore, SDF with HPMC prepared by the new method was still stable after stored at 40degreesC for 3 months. The pharmacokinetic parameters after oral administration in monkeys showed no significant difference (P &gt; 0.01) between SDFs with HPMC prepared by the two methods. In conclusion, we have established the new preparation method for SDF of tacrolimus with HPMC and the new method makes it possible to prepare SDF of tacroliumus without dichloromethane. (C) 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2003.07.010

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

1. To elucidate the determining factors for elimination pathways of sulfate and glucuronide metabolites of xenobiotics, a single-pass perfusion of 4-methylumbelliferone (4MU) or p -nitrophenol (pNP) was performed with an isolated rat liver preparation.
2. Without bovine serum albumin in the perfusion system, clearance calculated based on the unbound concentration in the liver clearly showed that the net efflux clearances (CL eff ) of sulfates from the sinusoidal membrane were much higher than those of glucuronides and that the biliary excretion clearances (CLb ) of glucuronides were approximately two times larger than those of sulfates.
3. The ratios of CLeff to CLb were much higher for sulfates than those for glucuronides. The bile-oriented elimination of glucuronides or sinusoidal efflux-oriented elimination of sulfates was observed even using the perfusate including 3% bovine serum albumin, but the sinusoidal efflux of sulfates was extensively enhanced by bovine serum albumin in the perfusate. The mechanisms behind this stimulatory effect remain to be elucidated.
4. For both compounds, CLb of glucuronide was comparable with CLb of sulfate, meaning that CLb is not responsible for the biliary excretion of glucuronides at extensively higher rate than sulfates.
5. Higher concentration of glucuronides in the liver, partly caused by much lower CLeff of glucuronides than that of sulfates, is likely responsible for the bile-oriented excretion of glucuronides. The extensive sinusoidal efflux of sulfates, leading to the urine-oriented excretion, is attributed to the substantially higher CLeff than CLb .
6. In conclusion, the sinusoidal efflux is an important factor for determining elimination pathways of both sulfates and glucuronides, although further studies are needed to clarify the mechanisms of the sinusoidal efflux.

DOI： 10.1080/00498250310001615771

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

Purpose. To investigate the inhibitory activity of casein on proteases in detail, the effect of digested products of casein itself on trypsin and chymotrypsin in rat small intestine was examined.
Methods. Male Sprague-Dawley rats weighing 200 - 300 g were used as the animal model. The luminal content of the jejunum was prepared, and the enzymatic activities of trypsin and chymotrypsin were determined using a specific substrate for each protease. Then, the effect of enzymatic digested products of casein on them was examined.
Results. The inhibitory activity of trypsin-digested casein against trypsin decreased as its digestion proceeded, but its inhibitory activity against chymotrypsin came to be more effective. On the other hand, the inhibitory activity of chymotrypsin-digested casein against chymotrypsin decreased with the degree of digestion, but no change in the inhibitory activity against trypsin was observed. Even the completely digested products of casein with trypsin or chymotrypsin showed inhibitory activities against the two proteases.
Conclusions. It was suggested that not only the intact casein but also the products digested with trypsin or chymotrypsin contribute to the inhibitory effect of casein on the proteases in the intestinal lumen.

DOI： 10.1023/B:PHAM.0000003370.38861.2d

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

Purpose. The purpose of this work was to determine the jejunal permeability of cyclosporin A (CsA) in humans and whether formulation variables modulate the effects of P-glycoprotein (P-gp) on the permeability of CsA in Caco-2 cells.
Methods. A solution containing CsA, phenylalanine, propranolol, polyethyleneglycol ( PEG) 400, and PEG 4000 was perfused through a 10-cm jejunal segment in 12 subjects. Caco-2 transport studies were performed using previously reported methodology.
Results. The mean P-eff (+/-SD) of CsA in humans was 1.65 (0.53). The mean permeabilities for phenylalanine, propranolol, and PEG 400 were 4.54 (2.39), 2.90 (1.28), and 0.83 (0.51) x 10(-4) cm/s, respectively. The presence of surfactants significantly decreased the permeabilities of CsA in both directions in Caco-2 cells.
Conclusions. The results suggest that the effects of surfactants via micellar solubilization and inhibition of P-gp efflux on CsA transport in Caco-2 cells are significant. CsA can rightly be classified as a low solubility-high permeability Class II BCS drug and its highly variable absorption from Sandimmune(R) oral formulations is the result of poor dissolution characteristics.

DOI： 10.1023/A:1023481418576

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1. The liver is the target organ for the lipid-regulating effect of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, and liver-selective uptake of this drug is therefore a desirable property. The uptake kinetics of rosuvastatin were investigated and compared with those of pravastatin using isolated rat hepatocytes.
2. Uptake for both drugs involved both active transport and passive diffusion processes. The Michaelis constant (K-m) of uptake rate for rosuvastatin (9.17 muM) was approximately half that for pravastatin (16.5 muM). However, the maximum uptake rate (V-max) and carrier-mediated uptake clearance (V-max/K-m) of rosuvastatin were significantly (p &lt; 0.01) greater than those of pravastatin, and a larger contribution of carrier-mediated uptake clearance to total uptake clearance was shown for rosuvastatin (contribution ratio 0.903 versus pravastatin 0.654).
3. Sodium and chloride ions did not play a significant role in the uptake of rosuvastatin and pravastatin, but the uptake of both drugs was inhibited both by depletion of cellular ATP and by organic anions such as bromosulfophthalein.
4. Rosuvastatin competitively inhibited the uptake of pravastatin, with an inhibition constant (K-i) (2.75 &mu;M) relatively similar to its K-m.
5. The results suggest that an organic anion transport protein is the main mediator of the hepatic uptake of rosuvastatin and pravastatin, which occurs in an ATP-dependent manner. Our results indicated that rosuvastatin was taken up by the hepatocytes via the same transport systems as pravastatin, but with a greater affinity and efficiency than pravastatin.

DOI： 10.1080/0049825031000066259

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

Purpose. To investigate the possible use of casein as an adjuvant for oral delivery of peptide drugs, the inhibitory activity of casein on proteases in rat small intestine was examined.
Methods. Male Sprague - Dawley rats weighing 200 - 300 g were used as the animal model. The luminal contents of the small- intestinal tract and mucosal subcellular fractions of the small intestine were prepared; the enzymatic activities of trypsin, chymotrypsin, aminopeptidase-B, leucine aminopeptidase, dipeptidylaminopeptidase- IV, cathepsin B, and dipeptidylaminopeptidase- II were determined using a specific substrate for each protease; and the effect of casein on the protease activity was examined.
Results. Casein strongly inhibited trypsin and chymotrypsin in the concentration- dependent manner. As to the proteases in the intestinal epithelial cells, casein inhibited an endopeptidase, cathepsin B, but not other exopeptidases. The inhibitory activity was independent of the type of casein. The kinetic analysis characterized the type of inhibition on trypsin and chymotrypsin to be competitive.
Conclusions. Casein was shown to have strong inhibitory activity on trypsin and chymotrypsin in the intestinal lumen. Taken into consideration that trypsin and chymotrypsin are endopeptidases, it is suggested that casein has strong inhibitory activity only on endopeptidases.

DOI： 10.1023/A:1023298816392

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

We previously reported that the combinatorial use of sodium laurate (C12) with several amino acids such as taurine (Tau) and L-glutamine (L-Gln) enhanced the colonic absorption of phenol red with attenuating the local toxicity caused by C12. However, even these amino acids could not protect epithelial cells from being damaged if the mucosal damage got worse to the coagulation necrosis by an excessive dose of C12. Comparing C12 with sodium caprate (C10), used in drug products marketed, 100 mumol C10 was needed to exert the similar absorption-enhancement of rebamipide, a poorly absorbable antiulcer drug, to that by 10 mumol 012, and 100 mumol C10 was obviously more toxic to the mucosa than 10 mumol C12. The combinatorial use of C12 with Tau or L-Gln enhanced the colonic absorption of rebamipide four to nine times larger in AUC than the control. Histopathologic studies clearly showed that Tau and L-Gln exerted the cytoprotective action on epithelial cells suffering from slight damages such as shrinkage and exfoliation, more articulately at 6 h than at 1.5 h after dosing. In conclusion, the combinatorial use of C12 with Tau or L-Gln could lead to a novel formulation improving the bioavailability of poorly absorbable drugs without any serious local damages. (C) 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:911-921, 2003.

DOI： 10.1002/jps.10362

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The gastrointestinal-transit-absorption (GITA) model is useful for the analysis and the prediction of the absorption behavior of drugs orally administered as solutions. In the present study, we tried to predict the plasma concentration-time profile of a colon-targeted prodrug, salicylazosulfanilic acid (SASA), and its parent drug, 5-aminosalicylic acid (5-ASA) which is regenerated after dosing. Prediction of plasma concentration-time profiles for SASA and 5-ASA was performed based on the GITA model using parameters describing GI-transit kinetics, the absorption in each GI segment, and the regeneration of 5-ASA in cecum. Plasma concentration-time profiles of both SASA and 5-ASA after oral administration of SASA were predicted very well by introducing a factor for the first-pass elimination of 5-ASA into the GITA model. The simulation study using the parameters obtained in the present study showed that about 94.7% of SASA reaches the cecum, where 5-ASA is regenerated very rapidly and 76.0% of 5-ASA is absorbed. Furthermore, the bioavailability of 5-ASA was estimated to be 0.330 because of the first-pass elimination through both cecum and liver. In conclusion, the absorption behaviors of a prodrug and its regenerated parent drug can be predicted very well and be clarified successfully using the GITA model. (C) 2002 Elsevier Science B.V. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

Rosuvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. The liver is the target organ for the lipid-regulating effect of rosuvastatin; therefore liver-selective uptake of this drug is a desirable property. The aim of this study was to investigate, and compare with pravastatin and simvastatin, the tissue-specific distribution of rosuvastatin. Bolus intravenous doses (5 mg/kg) of radiolabeled rosuvastatin, pravastatin, and simvastatin were administered to rats, and initial uptake clearance (CLuptake)in various tissues was calculated. Hepatic CLuptake of rosuvastatin (0.885 ml/min/g tissue) was significantly (p &lt; 0.001)larger than that of pravastatin (0.703 ml/min/g tissue), and rosuvastatin was taken up by the hepatic cells more selectively and efficiently than pravastatin. Hepatic CLuptake of simvastatin (1.24 ml/min/g tissue) was significantly larger than that of rosuvastatin (p &lt; 0.01) and pravastatin (p &lt; 0.001). However, adrenal CLuptake of simvastatin (1.55 ml/min/g tissue) was larger than hepatic CLuptake, and simvastatin was distributed to other tissues more easily than rosuvastatin. Microautoradiography of the liver, spleen, and adrenal was undertaken 5 min after administration of the study drugs; distribution was quantified by counting the number of silver grains. After administration of rosuvastatin and pravastatin, silver grains were distributed selectively in the intracellular space of the liver, but more rosuvastatin (3.3 &PLUSMN; 1.0 &PLUSMN; 10(5) particles/mm(2)) than pravastatin (2.0 &PLUSMN; 0.3 &PLUSMN; 10(5) particles/mm(2)) tended to distribute to the liver. Simvastatin was less liver-specific (it also distributed to the spleen and adrenal). The results of this study indicated that rosuvastatin was taken up by hepatic cells more selectively and more efficiently than pravastatin and simvastatin.

DOI： 10.1124/dmd.30.11.1158

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

1. The distribution characteristics of clarithromycin to the lung were investigated in vivo and in isolated lung perfusion experiments. The in-vivo integration plot analysis showed that the pulmonary uptake and extracellular distribution in the lung were significantly higher for clarithromycin than for erythromycin.
2. In the rat lung single-pass perfusion study, the pulmonary extraction ratio (E-ss) of clarithromycin at steady-state was significantly higher than that of erythromycin, and the E-ss of clarithromycin tended to decrease as the inflow concentration increased, suggesting the involvement of carrier-mediated transport in the pulmonary disposition of clarithromycin.
3. The outflow patterns of clarithromycin or erythromycin at various inflow concentrations were simultaneously analysed based on a pharmacokinetic model, which consists of the non-specific binding site, the specific binding site and the subsequent uptake process. The parameters obtained suggested that clarithromycin would have the higher affinity and higher capacity for the specific binding site, and the higher equilibrium constant for the non-specific binding site than erythromycin.
4. The simulation study using those parameters demonstrated that clarithromycin could be bound to the specific binding site and subsequently taken up more extensively than erythromycin.
5. A multiple-indicator dilution study also indicated that clarithromycin was more readily associated and extracted with the lung than with erythromycin. In the inhibition study, it was suggested that the pulmonary uptake of clarithromycin could be ascribed not only to the non-specific binding depending on its lipophilic nature, but also in part to some specialized mechanisms such as organic cation transporters.

DOI： 10.1080/00498250210160741

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To elucidate the important factors for the difference in the hepatic disposition between polystyrene nanospheres with a size of 50 nm (NS-50) and lecithin-coated NS-50 (LNS-50), the liver perfusion studies and the in vitro uptake studies using the cultured Kupffer cells were performed. It was suggested that opsonin-mediated phagocytosis is not significantly involved in the hepatic disposition of LNS-50 in the presence of serum, whereas its involvement in the hepatic uptake of NS-50 was clearly demonstrated. Western blot analysis showed that IgG, complement C3, and fibronectin, well-known opsonins in the serum, adsorbed on the surface of NS-50 in larger amount than on the surface of LNS-50. On the other hand, serum albumin, which was suggested to function as a dysopsonin for the hepatic disposition of NS-50, was associated with both spheres almost to the same extent. These findings suggest that the hepatic disposition of LNS-50 at lower level should be ascribed to the less amount of serum opsonins associated on the surface and that the serum proteins associated with these spheres should be important as a determinant for their hepatic disposition. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0168-3659(02)00196-7

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To develop a more efficient transdermal delivery system. it is very important to regulate the intradermal disposition of drugs after topical application, We tried to elucidate the factors determining the intradermal disposition kinetics, especially drug penetration from the viable skin to the muscular layer, mainly based on the six-compartment model, including the contralateral skin and muscle for ten model drugs with different physicochemical characteristics, In vivo transdermal absorption study was performed for six model drugs using the stripped-skin rats. The fitting analyses by the six-compartment model gave the theoretical curves describing the observed data very well and the reasonable pharmacokinetic parameters, showing the pharmacokinetic model should be useful for the estimation of the intradermal disposition kinetics of drugs applied topically again. The simulation study using the pharmacokinetic parameters obtained above Could show the relative contribution of the direct penetration and the distribution from the systemic circulation to the muscular distribution of drugs. The largest contribution of direct penetration was observed for antipyrine (90.8%) and the smallest was for felbinac (43.3%). Among the pharmacokinetic parameters obtained above, the clearance from the viable skin to the muscle (CLvs-m) was found to be significantly correlated with the unbound fraction of drugs in the viable skin (fu(vs)). Although the clearance from the viable skin to the plasma (CLvs p) also tended to increase as fu(vs) increased, the ratio of CLvs-m to CLvs-p was significantly correlated with fu(vs), meaning that the larger amount of unbound drug in the viable skin significantly contributes to the direct penetration into the muscle more than to the systemic absorption. On the other hand, k(direct) values obtained in in vitro penetration study-the penetration rate constant of drugs from the viable skin to the muscular layer-were found to be correlated with CLvs-m values for seven model drugs. Therefore, adding the in vitro experiments for other three model drugs, the multiple linear regression analysis of k(direct) was performed for ten model drugs in terms of fu(vs), logarithm of the partition coefficient (Log P) and molecular weight. The results clearly showed the largest and significant contribution of fu(vs) to the direct penetration of drugs from the viable skin to the muscular layer, indicating that a drug with the higher value of fu(vs) in the viable skin can penetrate more into the muscular layer. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0378-5173(02)00084-4

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

1. The hepatic and renal handling of glucuronides and sulphates of three phenolic compounds, 4-methylumbelliferone (4-MU), p-nitrophenol (pNP) and acetaminophen (APAP), were evaluated pharmacokinetically by in vivo constant infusion experiments in rat. It was shown that the urinary excretion rate at steady-state was larger than the biliary excretion rate for both glucuronides and sulfates, and sulfates, in particular, were extensively excreted into the urine.
2. For each glucuronide, however, biliary excretion clearances (CLb) calculated based on the total concentration and unbound concentration in the liver were much larger than the corresponding renal excretion clearances (CLr). Even in the case of sulfates, there was not any large difference between CLr and CLb based on the total and unbound concentration in tissues, which could not explain their extensive urinary excretion. From these results, these excretion clearances were recognized not to reflect necessarily the actual excretion rate obtained.
3. On the other hand, the tissue-to-plasma concentration ratio (K-p) of both glucuronides and sulfates for every phenolic compound was much higher in the kidney than that in the liver. The results suggested that one of the most important determinants for the preferential excretion of these conjugates into the bile or urine is the extent of disposition of each compound to the liver or kidney.
4. In addition, K-p of both glucuronides and sulfates in the liver, where these conjugates are mainly formed, was small. The K-p of sulfates was quite low, suggesting that sulfates generated in the liver were subject to extensive sinusoidal efflux.

DOI： 10.1080/00498250210123094

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

Several amino acids, including L-glutamine (L-Gln), were found to protect the intestinal epithelial cells from the local toxicity caused by a drug absorption enhancer, sodium laurate (C12), in our previous study. To develop more efficient and safer formulations for enhancing drug absorption, the mechanisms of cytoprotection by amino acids were studied using rats and Caco-2 cells. Four amino acids, including L-Gln, could generally maintain the absorption-promoting action of C12, although taurine tended to attenuate it. Three amino acids, except for L-Gln, significantly suppressed the decrease in the transepithelial electrical resistance caused by C12. Quercetin, an inhibitor for biosynthesis of heat shock protein 70 (HSP70), masked only the protective effect of L-Gln in both rat large intestine and Caco-2 cells. Western blot analysis indicated clearly that HSP70 is induced extensively only by the addition of L-Gln in both rat large-intestinal cells and Caco-2 cells. C12 was found to increase the intracellular concentration of Ca2+ ([Ca2+](i)) remarkably, and amino acids, especially L-arginine, L-methionine, and taurine, significantly attenuated the increase in [Ca2+](i) caused by C12. Furthermore, although C12 stimulated the release of histamine, an inflammatory mediator, from rat large-intestinal tissue, amino acids were also found to suppress the release of histamine enhanced by C12. The results in the present study showed that an induction of HSP70, a decrease in [Ca2+](i) elevated by C12, and a suppression of histamine release stimulated by C12 should be involved in the mechanisms behind the cytoprotective action of amino acids against the local toxicity caused by C12. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/jps.10049

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Authorship：Last author   Language：English   Publisher：PHARMACEUTICAL SOC JAPAN  

The gastrointestinal (GI) absorption of orally administered drugs is determined by not only the permeability of GI mucosa but also the transit rate in the GI tract. It is well known that the gastric emptying rate is an important factor affecting the plasma concentration profile of orally administered drugs, and the intestinal transit rate also has a significant influence on the drug absorption, since it determines the residence time of the drug in the absorption site. The reason why the residence time is also a critical factor for drug absorption is that there is the site difference in absorbability for some drugs. We have developed the GI-Transit-Absorption Model (GITA Model) to analyze and predict the drug absorption kinetics by taking into account both the two factors, i.e. GI transit and drug absorbability including its site difference. GITA Model has been already evidenced to be very useful for estimating the absorption kinetics of drugs with various characteristics and applied to assess the human data in combination with the gamma scintigraphy. In this review, the importance of GI transit rate in determining the absorption kinetics and the bioavailability of orally administered drugs is discussed mainly employing GITA Model and the results obtained by the model.

DOI： 10.1248/bpb.25.149

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL PHARMACEUTICAL SOC GREAT BRITAIN  

To evaluate the role of several specialized mechanisms for D-glucose transport in human oral mucosa, a cultured stratified cell layer derived from human oral mucosa was employed. Although this culture system has been used for reconstructive surgery, we, for the first time, tried to apply this system to the evaluation of nutrients and drug transport. Cell number and transepithelial electrical resistance (TEER) reached steady state 7-8 days after inoculation on the Transwell and TEER values at steady state were 130-140 Omega cm(2), which was higher or lower than that of small intestine oar Caco-2 cells, respectively. The transport studies were carried out using the cultured epithelium on the Transwell. The transport of D-glucose across the cultured stratified layer of oral epithelial cells was much more extensive than L-glucose, and was inhibited by 2-deoxy-D-glucose, a substrate of facilitative glucose transporters, and alpha-methyl-D-glucoside, a specific substrate of a Na+/glucose cotransporter (SGLT1). The results indicate that the sugar transporters function not only to take up D-glucose by the epithelial cells but also to transport the sugar across the stratified epithelial layer.

DOI： 10.1211/0022357021778402

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The plasma concentration time profile of theophylline after oral administration in human volunteers was predicted using the individual gastrointestinal (GI) transit data monitored by a gamma scintigraphic technique. Theophylline was administered as aminophylline under fasted and fed condition, along with Tc-99m-labeled diethylenetriamine-pentaacetic acid (DTPA), an unabsorbable marker to evaluate the GI transit by a gamma scintigraphic technique. Two healthy male volunteers participated under fasted and fed conditions in a crossover study. The GI transit was evaluated by dividing the GI tract to four segments, stomach, jejunum, ileum and cecum/colon. Under the fed condition, the GI transit pattern for each segment was confirmed to alter considerably, causing a delay in the gastric emptying mainly. Further, the plasma concentration curves of theophylline after oral administration were predicted using the GI-Transit-Absorption Model on the basis of individual GI transit parameters calculated by the fitting of the observed data to the GI-Transit Kinetic Model. The absorption rate constant in each segment and the pharmacokinetic parameters after intravenous administration used for the prediction were the values extrapolated from the data in rats and the ones normalized from the values in literatures, respectively. The plasma concentration-time curves for theophylline were well predicted using obtained individual GI transit parameters. The analysis using this method could estimate the variable absorption behavior governed by the GI transit in detail. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0378-5173(01)00942-5

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Language：English   Publisher：BEGELL HOUSE INC  

The clearance of colloidal particles from the blood circulation occurs by phagocytes and/or endothelial cells, mainly in the liver, the spleen, and the bone marrow. The relative distribution of the injected particles in these organs is known to depend on various factors such as the size and surface properties of the particles and the type of serum proteins adsorbed onto the surface of particles. The basic principles behind their distribution characteristics into the reticuloendothelial system, however, remain unclear. This article reviews major determinants in hepatic disposition of polystyrene nanospheres, especially the relationship among physicochemical properties of the particle surface, the type of blood components associated onto the surface of particles, and their in vivo disposition characteristics in rats, and considerations to be given and implication for the rational design of particulate drug carriers are discussed.

DOI： 10.1615/CritRevTherDrugCarrierSyst.v19.i45.10

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Absorption behavior of theophylline, categorized into Class I of Biopharmaceutics Classiôcation System, orally administered as powders in rats was analyzed and predicted by Gastrointestinal-Transit-Absorption (GITA) model, which was modiôed to describe GI-transit kinetics and dissolution of powders orally administered. First of all, GI-transit kinetics of glass beads was examined to describe the transit kinetics of powders through GI tract in rats. The results showed that the gastric emptying of glass beads was slower than that of solution, but that there was not much diference in the transit rate constants through the small intestine and cecum between glass beads and solution. Furthermore, to introduce the dissolution process of theophylline powders into GITA model, an in-vitro dissolution test was examined for theophylline powders according to the Japanese Pharmacopoeia paddle method. The dissolution rate constants calculated based on the mean dissolution time were not so diferent in the range of pH from 1.2 to 6.5. Using the parameters for GI transit, dissolution and absorption obtained, the plasma concentration-time proôle of theophylline after oral administration as powders to rats was predicted based on GITA model. The proôle calculated was significantly correlated with the observed time course of plasma concentration for theophylline, and the parameters such as Cmax and AUC based on the predicted curve coincided with those on the observed data, showing that GITA model is useful for the prediction of the absorption behavior of drugs administered as powders. The simulation studies showed that about 80z of orally administered theophylline powders dissolved in the stomach and that the remaining powders rapidly moved to the lower jejunum and ileum, where they dissolved. Furthermore, it was suggested that theophylline is absorbed mostly in the upper small intestine, duodenum, upper jejunum and lower jejunum, after its oral administration as powders. © 2002, The Japanese Society for the Study of Xenobiotics. All rights reserved.

DOI： 10.2133/dmpk.17.307

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The in vivo disposition of polystyrene microsphere (MS) with the particle size of 50 run (MS-50) and lecithin-coated MS-50 (LMS-50) after intravenous administration to rats was characterized. While a rapid elimination from the systemic circulation was observed for MS-50, much more prolonged circulating property was observed for LMS-50. In addition, this in vivo disposition property of LMS-50 was suggested to be ascribed to its lower affinity to the liver, which is the determining organ of the in vivo disposition of MS-50. The evaluation of surface hydrophobicity of MS-50 and LMS-50 in buffer solution revealed that the surface of MS-50 is more hydrophobic than that of LMS-50. However, LMS-50 was oppositely found to be more hydrophobic than that of MS-50 in rat serum. The profiles of serum proteins associated with MS-50 and LMS-50 were also examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The results showed that the amounts of some adsorbed proteins are greatly different between MS-50 and LMS-50. From these findings, it was suggested that the substantial difference in the in vivo disposition between MS-50 and LMS-50 would not be attributed to the difference in their surface hydrophobicity in the blood, but the difference in the type of serum proteins associated with them. (C) 2001 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0168-3659(01)00468-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

The proton-coupled oligopeptide transporter (PEPT1) has been shown to mediate mucosal cell transport of di- and tripeptide, and some peptidomimetic drugs. In this study, we determined the correlation between PEPT1 protein expression and the permeability of cephalexin, a substrate of PEPT1, in human PEPT1 (hPEPT1)-overexpressed Caco-2 cells (Caco-2/hPEPT1 cells) and rat jejunum. Caco-2/hPEPT1 cells with various levels of hPEPT1 expression were established by an adenoviral transfection system. The effective intestinal permeability (P-eff) in rat jejunum was evaluated using a single pass in situ perfusion method. The level of PEPT1 in Caco-2/h1PEPT1 cells and rat intestinal mucosal samples was quantitated by densitometry after immunoblotting and enhanced chemiluminescence detection. In Caco-2/hPEPT1 cells, an excellent correlation was observed between cephalexin uptake and hPEPT1 expression (R-2 = 0.96, P &lt; 0.005). This demonstrates that cephalexin uptake is directly proportional to hPEPT1 expression. In the rat per-fusion study, the mean P-eff +/- S.D. (n = 15) of cephalexin was 3.89 +/- 1.63 x 10(-5) cm/s. A very significant correlation between PEPT1 expression and cephalexin permeability with an R-2 = 0.63 (P &lt; 0.001) was observed. This indicates that the variation in PEPT1 expression is one of the major factors accounting for variable intestinal cephalexin absorption. To our knowledge, this is the most direct evidence that variation of PEPT1 expression is correlated with absorption permeability variation of peptide-like compounds in vitro and in vivo.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

To develop the safe absorption-enhancing formulation attenuating the local toxicity caused by an absorption enhancer, sodium laurate (C12), the effects of amino acids on the local toxicity by C12 were examined in rats. The absorption of phenol red, an unabsorbable marker drug, was significantly enhanced by 10 mM C12 in an in situ colon loop study and the addition Of L-glutamine (L-Gln), L-arginine, or L-methionine at 10 mM did not change the promoting effect of C12. However, C12 significantly increased the elution of phospholipids, total protein, and lactate dehydrogenase, which are markers for local toxicity, from colon, but these amino acids attenuated the local toxicity caused-by C12 significantly. Transport study using an Ussing-type chamber showed that the permeability of colonic membrane to phenol red was significantly enhanced by C12 and that L-Gln did not decrease the permeability enhanced by C12. Transmucosal electrical resistance was extensively decreased by C12, indicating that C12 could enhance the drug absorption at least partly by expanding the paracellular route. L-Gln significantly, but not completely, recovered resistance lowered by C12. Electrical potential difference was markedly reduced by C12, suggesting that C12 lowered the viability of mucosal cells, but 10 MM L-Gln significantly recovered potential difference almost to the control level. These results suggested the possibility that absorption-enhancing formulation with low local toxicity, which is low enough to be used practically, could be developed by using an amino acid like L-Gln as an ingredient attenuating the local toxicity caused by C12. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.

DOI： 10.1002/jps.1097

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Hepatic uptake and bilialy excretion of fluorescein isothiocyanate-labeled polystyrene microspheres with a particle size of 50 nm (MS-50) were studied in rats. Liver perfusion studies revealed that not only apo-E-mediated but also asialoglycoprotein receptor-mediated uptake is involved in the mechanism of the serum protein-dependent uptake of MS-50 in the liver. The uptake of MS-50 mediated by apo-E contributes more to the total uptake of MS-50 by the hepatocytes than that via asialoglycoprotein receptor in the presence of serum in the perfusate. Furthermore, it was found that MS-50 is substantially excreted into the bile by transcytosis. The extent of exocytosis of MS-50 taken up by the hepatocytes was much higher after MS-50 was endocytosed via asialoglycoprotein receptor than after taken up via the process mediated by apo-E. On the basis of these results, a possible regulation of the intracellular sorting of ligands, depending on the receptor-mediated uptake mechanism, was inferred. (C) 2001 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0304-4165(01)00132-5

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

The plasma concentration-time profiles following oral administration of drugs are often irregular and cannot be interpreted easily with conventional models based on first- or zero-order absorption kinetics and lag time. Six new models were developed using a time-dependent absorption rate coefficient, k(a)(t), wherein the time dependency was varied to account for the dynamic processes such as changes in fluid absorption or secretion, in absorption surface area, and in motility with time, in the gastrointestinal tract. In the present study, the plasma concentration profiles of propranolol obtained in human subjects following oral dosing were analyzed using the newly derived models based on mass balance and compared with the conventional models. Nonlinear regression analysis indicated that the conventional compartment model including lag lime (CLAG model) could not predict the rapid initial increase in plasma concentration after dosing and the predicted C-max values were much lower than that observed. On the other hand, all models with the time-dependent absorption rate coefficient, k(u)(t), were superior to the CLAG model in predicting plasma concentration profiles. Based on Akaike's Information Criterion (AIC), the fluid absorption, model without lag time (FA model) exhibited the best overall fit to the data. The two-phase model including lag time, TPLAG model was also found to be a good model judging fr om the values of sum of squares. This model also described the irregular profiles of plasma concentration with time and frequently predicted C-max, values satisfactorily. A comparison of the absorption rate profiles also suggested that the TPLAG model is better at prediction of irregular absorption kinetics than the FA model. In conclusion, the incorporation of a time-dependent absorption rate coefficient k(a)(t) allows the prediction of nonlinear absorption characteristics in a more reliable manner.

DOI： 10.1023/A:1011573831444

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

The gastrointestinal (GI) transit and absorption of orally administered theophylline, a highly absorbable drug without presystemic elimination, were investigated under fasted and fed conditions using three rats in a crossover study. To evaluate the GI transit rate for each segment in vivo, a noninvasive technique, gamma scintigraphy, was employed using a nonabsorbable compound, Tc-99m-labeled diethylenetriamine pentaacetic acid (DTPA). Using a gamma scintigraphic technique it is possible to simultaneously evaluate the GI transit and absorption of orally administered drug in the same individual. Theophylline was simultaneously administered along with [Tc-99m]DTpA to animals in the fasted and fed states. Each GI transit pattern, simulated using the GI transit-kinetic model with a lag time factor, was well fitted to the experimental data. Gastric emptying rate varied in each study, even under the same experimental condition. The GI transit pattern for each segment was highly variable, especially in animals in the fed state. This inconsistency in transit pattern was mainly due to the variability in gastric emptying, which was much slower in animals in the fed compared with the fasted state. However, in spite of a large variability of GI transit kinetics, the plasma concentration-time curves of theophylline were well predicted by the GI transit-absorption model using the individual GI transit parameters obtained in the study. The absorption rate of theophylline was considerably reduced in animals in the fed state, because of the reduction of gastric emptying rate. Analysis using GI transit-absorption model and gamma scintigraphic technique made it possible to estimate the variable absorption kinetics regulated by GI transit with huge variability. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:464-473, 2001.

DOI： 10.1002/1520-6017(200104)90:4<464::AID-JPS1004>3.0.CO;2-C

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：P J D PUBLICATIONS LTD  

The absorption enhancement by the sodium salts of several fatty acids was investigated in rat large intestine for model compounds having a wide range of molecular weight. Sodium caprylate (C8), sodium caprate (C10), sodium laurate (C12), which are categorized in medium-chain fatty acid, and sodium oleate (C18:1), long-chain unsaturated fatty acid, were employed as lipoidal adjuvants. Phenol red (MW=354.4), glycyrrhizin (822.9), fluorescein isothiocyanate-dextran-4 (FD-4, 4400), FD-10 (9400) and FD-40 (38900) were selected as model compounds for the assessment of the enhancing effect of the lipoidal adjuvants. The absorption of phenol red was promoted at the highest level, about 20 times higher by C12 and C18:1 than the control. The absorption rate - time profiles calculated by deconvolution method showed that C12 takes effect most rapidly and efficiently. In the case of glycyrrhizin, four adjuvants including C12 showed almost the same improvement of the absorption, about 30-40 times larger than the control. C8 and sodium citrate did not significantly enhance the absorption of those model compounds. For FD-4, FD-10 and FD-40, C10, C12 and C18:1 revealed almost the same enhancing effect and the absorption of FD-4, FD-10 and FD-40 was enhanced about 80 times, 1000-1800 times and about 200 times, respectively, larger than the control. The enhancement ratio, the ratio of AUC with adjuvant to AUC of control, suggests that these lipoidal adjuvants would improve most efficiently the absorption of the compound having the molecular weight of around 10000. Furthermore, C12 was suggested to be an effective adjuvant for the compounds with the wide range of molecular weight.

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Language：English   Publisher：The Japanese Society for the Study of Xenobiotics  

To develop the absorption enhancing formulation with local toxicity low enough for the practical use, we have investigated the effect of amino acids on the local toxicity and the absorption enhancement caused by sodium laurate (C12), used as an absorption enhancer. As a result, the absorption of phenol red (PR), an unabsorbable marker, was enhanced significantly by applying 10 mM C12 and the addition of amino acids did not change this absorption-enhancing effect of C12 in in situ colon loop study. On the other hand, although C 12 significantly increased the elution of phospholipids, proteins, and lactate dehydrogenase from colon, which are biological markers for local toxicity, amino acids significantly attenuated this mucosal injury caused by C12. In the present study, we tried to elucidate the mechanism involved in the protective effects of amino acids against mucosal injury caused by C12, and HSP70 was suggested to be involved in the cytoprotection by L-glutamine. Furthermore, the attenuation of intracellular Ca²⁺level and of histamine release, which are enhanced by C12, were also suggested to be mechanisms behind the cytoprotective action of amino acids.

DOI： 10.2133/dmpk.16.supplement_122

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

The prediction method for the plasma concentration-time profile of N-methyltyramine (NMT), a potent stimulant of gastrin release present in beer after oral ingestion in rats was examined using the previously developed Gastrointestinal (GI)-Transit-Absorption Model, with the addition of a process of hepatic first-pass metabolism. Phenol red was used as a nonabsorbable marker for estimation of the GI transit rate constant for eight segments in the GI tract. The first order absorption rate constant for each segment was estimated by means of a conventional in situ closed loop method. The results of in situ absorption experiments showed that NMT is well absorbed in the small intestine, especially in the duodenum and jejunum. Using the GI-Transit-Absorption Model, it was demonstrated that more than 90% of orally ingested NMT is absorbed in the small intestine, and that the substantial absorption site for NMT in vivo is the lower jejunum and the ileum. However, the observed bioavailability was only 39.0%. The in vitro metabolism study clarified that NMT is metabolized in the liver, but not in the small-intestinal mucosa. With the hepatic intrinsic clearance value (2.0 liters/h) calculated from the rate of metabolism in vitro, the hepatic availability was estimated to be 0.510 on the basis of a well stirred model, which was validated by two other methods to calculate the hepatic availability of NMT. The plasma concentration-time curve and bioavailability of NMT after oral ingestion were well predicted by the GI-Transit-Absorption Model with the hepatic first-pass metabolism process.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC PHARMACEUTICAL SCIENTISTS  

The proton-dependent oligopeptide transporters (POT) gene family currently consists of similar to 70 cloned cDNAs derived from diverse organisms. In mammals, two genes encoding peptide transporters, PepT1 and PepT2 have been cloned in several species including humans, in addition to a rat histidine/peptide transporter (rPHT1). Because the Candida elegans genome contains five putative POT genes, we searched the available protein and nucleic acid databases for additional mammalian/human POT genes, using iterative BLAST runs and the human expressed sequence tags (EST) database. The apparent human orthologue of rPHT1 (expression largely confined to rat brain and retina) was represented by numerous ESTs originating from many tissues. Assembly of these ESTs resulted in a contiguous sequence covering similar to 95% of the suspected coding region. The contig sequences and analyses revealed the presence of several possible splice variants of hPHT1. A second closely related human EST-contig displayed high identity to a recently cloned mouse cDNA encoding cyclic adenosine monophosphate (cAMP)-inducible 1 protein (gi:4580995). This contig served to identify a PAC clone containing deduced exons and introns of the likely human orthologue (termed hPHT2). Northern analyses with EST clones indicated that hPHT1 is primarily expressed in skeletal muscle and spleen, whereas hPHT2 is found in spleen, placenta, lung, leukocytes, and heart. These results suggest considerable complexity of the human POT gene family, with relevance to the absorption and distribution of cephalosporins and other peptoid drugs.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Our previous studies have demonstrated that serum would play an important role in the hepatic disposition of polystyrene microspheres (MS) and that complement C3 should be involved as the serum opsonin. In this study, we tried to identify the entity of other serum opsonins and dysopsonin for the hepatic uptake of MSs with particle sizes of 50 nm (MS-50) and 500 nm (MS-500) by isolated liver perfusion studies using a recirculation procedure in rats. Pretreatment of the liver by trypsin significantly suppressed the serum-dependent hepatic uptake of both MSs, suggesting that some protein components on the cell surface should be necessary for the serum-dependent phagocytosis of MSs. Pretreatment of the serum by the anti-fibronectin antibody resulted in a significant reduction in the hepatic disposition of MS-500 (49% of control), suggesting that fibronectin should also work as the opsonin for the hepatic uptake of MS-500. The hepatic disposition of both MSs in the presence of serum was inhibited by the addition of N-acetylgalactosamine into the perfusate, suggesting the possible involvement of lectin in the serum-dependent hepatic uptake of MSs, Furthermore, a more intensive hepatic disposition of MSs was observed in the presence of plasma compared with that in the presence of serum in the perfusate, suggesting the possible involvement of blood coagulation factors, such as fibrinogen, as the opsonin in the hepatic disposition of MSs. (C) 1999 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0304-4165(99)00116-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To study the mechanisms of the hepatic disposition of polystyrene microspheres (MS), effects of serum on their hepatic disposition characteristics were investigated for MSs with particle sizes of 50 nm (MS-50) and 500 nm (MS-500) by isolated liver perfusion experiments. It was revealed that serum in the perfusate inhibited and promoted the hepatic disposition of MS-50 and MS-500 at 37 degrees C, respectively. However, pre-heating at 56 degrees C or pre-treatment with anti-C3 antibody of serum reduced the promotive effect of serum on the hepatic uptake of MS-500, suggesting that the complement system should be involved as opsonins for the hepatic uptake of MS-500. Hepatic disposition of both MSs at 4 degrees C was reduced by the addition of serum into the perfusate, which could be ascribed to the reduction of the surface hydrophobicity of MSs due to the adsorption of serum proteins onto the surface of MSs and to resultant decrease in non-specific disposition to the liver. From these results, serum was found to function both as the opsonin to enhance the hepatic uptake of MSs and as the inhibitor by reducing non-specific interaction between MSs and the plasma membrane. Whether serum promotes or inhibits the hepatic disposition of MSs would be dependent on the particle sizes of MSs. (C) 1999 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0168-3659(99)00121-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The in vitro uptake study was performed using the isolated cells of human oral mucosa, buccal and the dorsum of the tongue, to investigate the mechanisms of glucose uptake. The uptake of D-glucose was much larger in cells of the dorsum of the tongue than in buccal cells and was inhibited more extensively by 2-deoxy-D-glucose, a substrate of facilitative glucose transporters, than by alpha-methyl-D-glucoside, a specific substrate of SGLT1, suggesting the larger contribution of a facilitative transporter than Na+/glucose cotransporter. Furthermore, from the results of inhibition studies by several sugar analogues including maltose and D-mannose, GLUT1 and/or GLUT3 were suggested to take part in the glucose uptake by oral mucosa. Therefore, we have attempted to confirm the expression of glucose transporters on the oral mucosa by employing Western blotting. As a result, it was suggested that SGLT1, GLUM, GLUT2, and GLUT3 are expressed in the epithelial cells of human oral mucosa.

DOI： 10.1021/js980298f

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The in vivo disposition of polystyrene microsphere (MS) with the particle: size of 50 nm (MS-50) or 500 nm (MS-500) was characterized after intravenous administration to rats. A rapid elimination from systemic circulation was observed for both MSs. Tissue distribution of MS-50 and MS-500 at 1 h after intravenous injection indicated that both MSs were exclusively distributed to liver and that small but significant amounts of. MS-50 and MS-500 were also distributed to lung and spleen, respectively. To investigate the intrahepatic distribution of MS, liver was separated into liver parenchymal cells (PC) and non-parenchymal cells (NPC) at 1 or 6 h after intravenous administration. The contribution of each cell fraction was dependent on both the size of MS and the lime after administration. Furthermore, by separating the NPC into endothelial cells and Kupffer cells using a centrifugal elutriation method, their contribution was also evaluated. For both MSs, Kupffer cells were recognized to be mostly responsible for the hepatic uptake, although a significant amount of MS-50 (about 28% of total uptake) was taken up by PC. On the other hand, there was little contribution of PC (about 5%) to the hepatic uptake of MS-500. The endothelial cells were contributed larger to the uptake of MS-500 (about 24%) than that of MS-50 (13%). (C) 1999 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0168-3659(99)00015-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

Purpose. The objectives of dermal application of drugs are not only systemic therapeutics, but also local ones. We would expect its intradermal kinetics to be dependent on its therapeutic purpose. To develop more efficient drugs for local or systemic therapeutics, it will be important to estimate quantitatively the intradermal disposition of drugs applied topically. We tried, therefore, to develop the compartment model to describe the intradermal disposition kinetics after topical application of drugs.
Methods. In vivo percutaneous absorption study for antipyrine, a model compound, was performed using rats with tape-stripped skin, using the assumption that the stratum corneum permeability to drugs would be improved enough not to be a rate-limiting process.
Results. To analyze the results obtained, a 4-compartment model, composed of donor cell, viable skin, muscle, and plasma compartments, was applied. Although the fitting lines obtained could describe the concentration-time profiles of antipyrine in each compartment very well, the concentration profiles in the contralateral tissues were extensively overestimated. Therefore, we developed a 6-compartment model which included the viable skin and muscle in the contralateral site, and analyzed the concentration-time curve of each compartment. The fitting curves were in good agreement with the experimental data for all the compartments including the contralateral viable shin and muscle, and thus, this model was recognized to be adequate for the estimation of intradermal kinetics after topical application. Judging from the obtained values of clearance from viable skin to plasma and from viable skin to muscle, about 80% of antipyrine penetrated into viable skin, which suggested it was absorbed into circulating blood and 20% was transported to muscle under viable skin.
Conclusions. Pharmacokinetic analysis using the 6-compartment model would be very useful for the estimation of local and systemic availability after topical application of drugs.

DOI： 10.1023/A:1018844928818

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：HARWOOD ACAD PUBL GMBH  

The in vivo uptake by hepatocytes and biliary excretion of fluorescein isothiocyanate-labeled polystyrene microsphere with a. particle size of 50 nm (MS-50) after intravenous administration was studied in rats. It was confirmed by using confocal laser scanning microscopy that MS-50 was partially phagocytosed by the hepatocytes and that MS-50 taken up by the hepatocytes existed exclusively inside the cells Ih after intravenous administration. Studies on the mechanism of the uptake of MS-50 by the hepatocytes using the liver perfusion technique revealed that a process mediated by apo-E was involved. After intravenous administration of MS-50, about 4% of dose was excreted into bile in 24 h, Pharmacokinetic evaluation of the excretion rate of MS-50 into bile showed that the process followed first-order kinetics. Qualitative evaluation of the fluorescence detected in the bile after intravenous administration of MS-50 revealed that the particles were certainly excreted into bile in an intact form, From these results, it was suggested that intravenously administered MS-50 would be partially phagocytosed by hepatocytes through a process mediated by apo-E and that MS-50 ingested by hepatocytes would be partially excreted into the bile.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

The factors determining drug residence in skin during penetration across rat abdominal skin were investigated using five beta-blocking agents with different lipophilicities as model drugs in vivo and in vitro. The amount of beta-blocking agent in the skin at steady state correlated well with lipophilicity. The distribution of beta-blocking agents to the stratum corneum and the contribution of intercellular lipids in the stratum corneum to their skin distribution were also correlated with their lipophilicity, suggesting that the stratum corneum, especially intercellular lipids in the stratum corneum, would be responsible for the residence of beta-blocking agents in the skin. Furthermore, cholesterol-3-sulfate, palmitic acid, stearic acid and oleic acid were found to interact with the beta-blocking agents, which are cationized under the physiological condition, and were assumed to play an important role in the skin accumulation. On the other hand, the binding to keratinocyte was so small that keratinocyte might have little effect on the skin accumulation of the beta-blocking agents. Drug transport from the stratum corneum to viable skin was suggested to be regulated by the lipophilicity of these agents. To investigate the residence of these drugs in viable skin, in vitro transport studies using stripped skin were performed. The transport rate constant across viable skin to receptor cells (k(23)) was inversely correlated with the lipophilicity of the drugs. The elimination rate constants from viable skin (k(vs)) obtained in the in vivo study were much smaller than the values of k(23) obtained in the in vitro study, and they were inversely correlated with the binding to cytosol components of viable skin but not the lipophilicity. The viable skin-to-muscle concentration ratio of these drugs, obtained at the beta-phase of the plasma concentration-time curve after intravenous administration, was also inversely correlated with the binding to the cytosol components of viable skin. These results suggest that k(vs) reflects the transport from viable skin to muscle rather than to blood circulation and that the binding of drugs to cytosol components in viable skin would be one of the important factors determining the residence in viable skin.

DOI： 10.1248/bpb.21.1195

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Two types of poly(vinyl alcohol)-gel spheres were prepared with chitosan (CS/PVA-GS) and without chitosan (PVA-GS), and comparative studies were performed using these gel spheres (GSs). No change in particle size was observed by the addition of chitosan: nearly 45% of both particles were in the 5-10 mu m range. In an in vivo gastrointestinal transit test, CS/PVA-GS prolonged the small-intestinal transit time more than PVA-GS. In an in vitro intestinal perfusion study, the mean transit time of these GSs was markedly reduced by pretreatment of the intestinal surface with a mucolytic agent, N-acetyl-L-cysteine, suggesting that the mucous layer on the intestinal surface plays an important role in controlling the transit rate of these GSs. The oral administration of aminophylline (theophylline) and ampicillin as model drugs incorporated in PVA-GS and CS/PVA-GS was examined in rats. While theophylline absorption from PVA-GS was not affected by the addition of chitosan, the improvement of ampicillin absorption by PVA-GS was enhanced by the chitosan combination.

DOI： 10.1248/bpb.21.1202

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHARMACEUTICAL ASSN  

The effect of gastrointestinal (GI) transit rate on the absorption behavior of orally administered drugs was investigated using rats pretreated with propantheline. The propantheline-treatment reduced the transit rate in all segments to approximately 50%. The absorption behavior was examined for three model drugs with different absorption characteristics: theophylline as a highly absorbable drug without the first-pass elimination, ampicillin as a poorly absorbable one, and cephalexin as a highly absorbable one via carrier-mediated transport system. In the GI transit-retarded state, the T-max of the plasma concentration-time curve was delayed in all the three drugs. However, the extent of bioavailability was not changed in theophylline and cephalexin. On the other hand, the extent of bioavailability of ampicillin was increased in rats pretreated with propantheline. This might be caused by the increased residence time in the absorption site, i.e., small intestine. These results were generally predicted by use of the convolution method based on the GI-Transit-Absorption Model, which was developed in our previous study, using the GI transit rate parameters in rats pretreated with propantheline. The analysis using this model could clarify that the substantial absorption site of cephalexin moved to the upper region of the small intestine by the reduction of the GI transit rate.

DOI： 10.1021/js980117+

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

1. The pharmacokinetics of a novel benzodiazepine partial inverse agonist (S-8510) were studied in the Fischer 344 (F344) rat and B6C3F1 mouse to obtain information for the planning of carcinogenicity studies. Sprague-Dawley (SD) rats were also included for comparison.
2. Clear non-linear elimination of S-8510 was observed after single oral administration of S-8510 in all animals tested (F344 rat, 1-50 mg/kg; SD rat and B6C3F1 mouse, 1-150 mg/kg).
3. Exposure of S-8510 after single oral administration was in the order F344 rat &gt; B6C3F1 mouse &gt; SD rat.
4. Multiple oral administration to F344 rat and B6C3F1 mouse decreased the exposure to S-8510.
5. These results indicate that it is very important to evaluate pharmacological and toxicological studies based on exposure and to be careful in selecting the species and strains of animal used in toxicology studies.

DOI： 10.1080/004982598239434

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHARMACEUTICAL ASSN  

The intestinal transport of quinidine was characterized in rat small intestine, using the Ussing-type chamber under short-circuited conditions. In the short-circuited condition, quinidine transport was predominantly secretory and the transport rate in jejunum was 3.5 times larger in the secretory direction than that in the absorptive direction. The secretion of quinidine was found to be dependent upon its concentration and to be via a carrier-mediated system in both jejunum and ileum. Although the kinetic characteristic of the carrier-mediated secretion of quinidine was very similar in jejunum and ileum, its contribution was much greater in jejunum because of a higher passive diffusion component in ileum. The secretion of quinidine, well-known as an inhibitor of P-glycoprotein, was inhibited significantly and its absorption was enhanced significantly by several substrates of P-glycoprotein including verapamil, diltiazem, and digitoxin in jejunum. These phenomena were also observed by the addition of 2,4-dinitrophenol. Furthermore, the voltage-clamp studies indicated that the inhibition of quinidine secretion occurred in the transcellular pathway. On the other hand, neither tetraethylammonium nor p-aminohippuric acid affected the transport of quinidine. Quinidine was also recognized to inhibit the secretion and to promote the absorption of substrates of P-glycoprotein, chlorpromazine, and verapamil. These results strongly suggest that quinidine is not only an inhibitor but also a substrate of P-glycoprotein and that the P-glycoprotein-mediated secretory flux acts as a barrier to quinidine absorption in the small intestine, especially jejunum.

DOI： 10.1021/js970294v

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

To clarify which process in renal secretion is responsible for the stereoselective renal secretion of organic anions, the renal handling of enantiomers of 5-monomethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (MBCA) was studied by the multiple-indicator dilution method, using isolated perfused rat kidney. After bolus injection of (R)-(+)-[C-14]MBCA or (S)-(-)-[C-14]MBCA into the renal artery, the outflow patterns for the perfusate and the urinary excretion rate profiles were estimated by statistical moment analysis. AUC values and mean transit times in kidney for the MBCA enantiomers indicated that (R)-(+)-MBCA was excreted much more extensively in urine and that it had a higher affinity for renal tissue than did (S)-(-)-MBCA. A significantly larger intrinsic clearance of secretion for (R)-(+)-MBCA attested to the R-(+)-preferential renal secretion. The uptake rate constant across the basolateral membrane, the ratio of the uptake rate constant to the free fraction in the perfusate, and the intracellular distribution volume were significantly larger for (R)-(+)-MBCA than for (S)-(-)-MBCA, indicating that uptake across the basolateral membrane and intracellular distribution were R-(+)-preferential, However, the mean time across renal epithelial cells for secreted molecules, the single-pass mean residence time in renal epithelial cells, and the rate constant for secretion across the brush-border membrane were not significantly different between enantiomers. The simultaneous presence of (R)-(+)-MBCA decreased the intrinsic clearance of secretion, the ratio of the uptake rate constant to the free fraction in the perfusate, and the intracellular distribution volume for (S)-(-)-[C-14]MBCA, although the secretion rate constant, the mean time across renal epithelial cells for secreted molecules, and the single-pass mean residence time in renal epithelial cells were not influenced by (R)-(+)-MBCA, confirming that uptake across the basolateral membrane and intracellular distribution were stereoselective processes.

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Language：English   Publisher：The Japanese Society for the Study of Xenobiotics  

Colloidal particles are good candidates for efficient drug carriers. However, the rapid clearance by macrophages of the reticuloendothelial system (RES), mainly Kupffer cells of liver and to a lesserextent macrophages of the spleen and the bone marrow, limits their application as carriers to other tissues and/or cells. To achieve a rational design of particulate carrier system, the basic information about in vivo disposition and the uptake mechanisms by RES of particle itself should be required. Therefore, in the present study, the in vivo disposition of polystyrene microsphere (MS) with the particle size of 50 nm (MS-50) or 500 nm (MS-500) was characterized after intravenous administration to rats. To study the mechanisms of the hepatic disposition of MSs, effects of serum on their disposition were investigated for both MSs by isolated liver perfusion experiments in rats. From these studies, it was found that serum would function both as opsonin to enhance the hepatic uptake of MSs and as inhibitor by reducing non-specific interaction between MSs and the plasma membrane. Whether serum promotes or inhibits the hepatic disposition of MSs would be dependent on the particle sizes of MSs.

DOI： 10.2133/dmpk.13.supplement_112

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILLIAMS & WILKINS  

The GI absorption of recombinant human insulin-like growth factor-I (rhIGF-I) and its improvement were investigated in rats. The I-125-rhIGF-I rapidly degraded to the trichloroacetic acid-soluble form in the small-intestinal contents, but it was relatively stable in the gastric and large-intestinal contents and in the subcellular fraction of the small-intestinal mucosa. To protect rhIGF-I from degradation in the small-intestinal contents, the effect of some adjuvants was examined and their degradation was markedly inhibited by the presence of aprotinin or casein. After p.o. administration of I-125-rhIGF-I at the dose of 1.0 mg/kg, trichloroacetic acid-precipitable radioactivity in the plasma was periodically determined. We found that a considerable amount of rhIGF-I was absorbed into the systemic circulation and that the bioavailability was 9.3%, which is much greater than that of insulin. The coadministration of aprotinin and that of casein enhanced the bioavailability further: 46.9% and 67.0%, respectively. Radioimmunoassay using a monoclonal antibody for rhIGF-I confirmed the high bioavailability of immunoreactive rhIGF-I. From gel chromatography of plasma, the radioactivity in the plasma was found to be in the form of high-molecular-weight complexes. The mechanism for the uptake of rhIGF-I by intestinal mucosa may be absorptive-mediated endocytosis.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILLIAMS & WILKINS  

Pharmacokinetics of recombinant human insulin-like growth factor-I (rhIGF-I) was investigated after iv administration (0.32, 1.0, and 3.2 mg/kg) to normal and streptozotocin-induced diabetic rats, rhIGF-I was eliminated from plasma biexponentially in both normal and diabetic rats, Plasma concentrations of rhIGF-I were lower at almost all the time points examined in diabetic rats than in normal rats. The pharmacokinetic parameters of total body clearance (CLtotal), mean residence time (MRT), and elimination rate constant (k(el)) indicated that rhIGF-I disappeared more rapidly In diabetic rats than in normal rats at any dosage. The amounts of IGF binding proteins (IGFBPs) in plasma were assessed by determining the endogenous IGF-I and. Levels of the 150 kDa complex, a ternary complex of IGF-I with IGFPB-3 and an acid-labile subunit, the 50 kDa complex, a complex of IGF-I with IGFBP-2, were found to be lower in diabetic rats than in normal rats, Fractions af rhIGF-I free and bound to the binding proteins were estimated by gel chromatographic separation of rhIGF-I in plasma after iv administration, and the pharmacokinetics of free and bound rhIGF-I was analyzed independently, Plasma concentrations of free and bound rhIGF-I were lower in diabetic rats than in normal rats, especially the concentrations of the 150 kDa complex were much lower. The reduced IGFBP-3 would be responsible for the faster elimination of rhIGF-I in diabetic rats.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：P J D PUBLICATIONS LTD  

Developmental changes in pharmacokinetics of recombinant human insulin-like growth factor-I (rhIGF-I) were investigated after i.v. administration to rats aged 4 and 7 weeks, as young growing rats and adult rats, respectively. rhIGF-I in the plasma declined multi-exponentially in both groups of rats. Plasma concentrations of rhIGF-I were lower at almost all the time points examined in 4 weeks old rats than 7 weeks old rats, The values of total body clearance (CLtotal) and mean residence time (MRT) indicated that rhIGF-I disappeared more rapidly in 4 weeks old rats than 7 weeks old rats at any dosage. Dose-dependent pharmacokinetics was observed in 7 weeks old rats: the higher the dosage was, the larger the value of CLtotal came to be, but not in 4 weeks old rats. The amounts of IGF-binding proteins (IGFBPs) in the plasma were assessed by determining the endogenous IGF-I, and the levels of the 150 kDa complex, a ternary complex of IGF-I with IGFPB-3 and an acid labile-subunit, were found to be lower in 4 weeks old rats than in 7 weeks old rats. In rats at 4 weeks of age, the elimination of rhIGF-I was significantly faster than for the 7 week old rats, which would be due to the lower plasma levels of IGFBP-3 in young growing rats.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL PHARMACEUTICAL SOC GREAT BRITAIN  

A new method based on gastrointestinal transit kinetics has been developed for estimation of the absorption profiles of drugs administered orally as aqueous solutions. The utility of the method was evaluated in rats.
The gastrointestinal transit profile for each segment was estimated by in-vivo studies using phenol red, an unabsorbable marker. The gastrointestinal transit profile of phenol red was well explained by a linear gastrointestinal transit kinetic model with eight segments. We also introduced the absorption process into the gastrointestinal transit kinetic model and the plasma profile was predicted by the convolution method. The absorbability of drugs in each segment was assessed by an in-situ absorption study. The validity of the model was evaluated for model drugs with different absorption characteristics. The plasma profiles predicted for ampicillin, theophylline and cephalexin were in good agreement with those observed. The overestimated plasma profile of propranolol suggests that the low bioavailability of propranolol is a result of first-pass metabolism by the intestine wall and the liver, because the calculated absolute absorption is almost perfect. This proposed model is also suitable for estimation of segmental absorption, which is useful for the development of drug delivery systems.
We have demonstrated that the plasma profile of orally administered drugs can be predicted by use of gastrointestinal transit and segmental absorbability information and that this method is especially useful for estimating separately the effect of absolute absorption and first-pass metabolism on the bioavailability of drugs.

DOI： 10.1111/j.2042-7158.1997.tb06823.x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

To improve the in vitro corneal transport of S-1033, a novel prostaglandin-derivative antiglaucoma medication, the effects of several factors such as benzalkonium chloride (BAC), concentration of S-1033, and lipophilicity on the corneal permeability of S-1033 were investigated. The apparent permeability coefficient (P-app) of S-1033 was 5.81 x 10(-7) cm/s on application of 0.1 mM solution. The addition of BAC (0.005%) enhanced by 2.5-fold the transport percent and P-app of S-1033. Corneal transport tended to be improved by methyl esterification of S-1033 but not by the coexistence of BAC with S-1033 methyl ester. TLC analysis showed that S-1033 methyl ester was hydrolyzed to S-1033 during passage through the cornea. The therapeutic concentration of S-1033 (5.4 mM, the highest concentration in the experiments), greatly promoted its transport and increased P-app. However, there was little difference in the uptake percent, which showed the transcorneal percent and corneal accumulation percent at steady state, for these dosing conditions. The highest concentration gave the lowest corneal accumulation percent and the highest corneal clearance, indicating that the transport rate of S-1033 in the cornea to the receptor side was the largest, which may have been responsible for the marked improvement of the transcorneal transport of S-1033. Increases in corneal accumulation of S-1033 due to methyl esterification and BAC addition seem to be due to the increase of lipophilicity and ion pair formation, respectively. To investigate the relationship between corneal permeability and the partition coefficient (PC) with or without BAC, the permeabilities of prostaglandin F-2 alpha (PGF(2 alpha)) and prostaglandin E(2) (PGE(2)) were estimated. The larger the value of logPC in the range of -0.67-3.89, the larger was the value of P-app in the absence of BAC. However, in the presence of BAC, there was a parabolic relationship, which suggests that BAC can greatly affect the interaction between cornea and drugs.

DOI： 10.1016/0378-5173(95)04372-1

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Language：English   Publisher：The Japanese Society for the Study of Xenobiotics  

The possibility of oral delivery of recombinant human insulin-like growth factor-I was investigated in rats. The degradation of ¹²⁵I-rhlGF-I in the gastrointestinal (GI) contents was in the order of jejunum = ileum >> large intestine, and little degradation was found in the stomach. Some adjuvants could inhibit the degradation, especially aprotinin and casein inhibited by 70-95%. On the other hand, rhlGF-I was relatively stable in the subcellular fraction of mucosal cells (BBM, cytosol, lysosome), and there was no site difference through the intestine. The bioavailability (BA) of rhlGF-I after oral administration was 9.3%, which was much greater than that of insulin. The BA was further increased by coadministration with aprotinin and casein, indicating that the stabilization of rhlGF-I in GI tract could enhance its absorption. From the results of gel filtration chromatography of rat plasma following oral administration of ¹²⁵l-rhIGF-I, the peaks in high molecular region were detected and they were thought to be macromolecular complexes which consist of ¹²⁵I-rhlGF-I and IGFBP-2 and/or -3. These results strongly suggest the possibility of oral delivery of rhlGF-I.<BR> We also examined the absorption kin etics of rhlGF-I by the in situ single-pass perfusion method. The absorption clearance (CLa) of rhlGF-I was dependent on its concentration. Using acid-washing technique, rhlGF-I was found to be adsorbed acid-sensitively to the mucosal surface and the incorporation of immunoreactive rhIGF-I to the mucosal tissue was recognized at the same time. These results suggest that rhlGF-I is absorbed partly by a specialized absorption mechanism.

DOI： 10.2133/dmpk.11.supplement_5106

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILLIAMS & WILKINS  

A prostaglandin derivative, (5Z,9 alpha,11 alpha,13E)-9,11 -dihydroxyprosta-5,13-dienoic acid sodium salt (S-1033), that lowers intraocular pressure with little adverse effect, may have clinical value in the treatment of glaucoma. After [C-14]S-1033 (0.2% solution) was instilled into the eye of a white rabbit, radioactivity and 5-1033 appeared in systemic plasma so rapidly (t(max) 5 min) and 5-1033 was eliminated very rapidly with half-lives of 2.8 and 11.0 min at alpha- and beta-phases, respectively. The metabolite, M-1, [1R-[alpha,2 beta-(1E),3 alpha,5 alpha]]-3,5-dihydroxy-2-(1- octenyl)-cyclopentanepropanoic acid (tetranor-S-1033), appeared in plasma very rapidly (t(max), 5 min), suggesting that a fast metabolism was a major factor in the rapid elimination of 5-1033 from plasma. The values for the ratios of the area under the curve of ocular instillation to intravenous administration for radioactivity and S-1033 were 1.01 and 0.52, respectively, indicating that more than half of the 5-1033 instilled was transported into the systemic circulation.
To clarify the contributing pathway of the massive and rapid systemic absorption of 5-1033 after topical dosing, plasma levels of S-1033 were investigated after instillation to rabbits in which the nasolacrimal ducts were occluded. Plasma concentrations of S-1033 were slightly higher than those in intact rabbits, suggesting that conjunctiva would be as important as nasal mucosae for the systemic absorption under the physiological condition.
As for the intraocular distribution, the highest levels of radioactivity were found in the cornea, conjunctiva, and anterior sclera. The uvea (iris and ciliary body), the probable target of 5-1033, and the aqueous humor also showed high levels of radioactivity. The distribution to the uvea, as shown by the area under the curve value, was largest after that of the cornea among ocular tissues, probably via the corneal route. S-1033 concentrations in aqueous humor 1 hr after dosing accounted for &gt;72% of the radioactivity, and tetranor-S-1033 accounted for almost all of the remainder.
The chemical structure of M-1 was determined by comparison of the mass spectra, retention times on gas chromatograms, and high-performance liquid chromatograms, and R(F) values on thin layer chromatographs with those of the synthesized compound.

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To clarify the stereoselective renal tubular secretion of an organic anion, renal excretion of 5-dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA), a racemic compound, was studied with a single-pass perfused rat kidney preparation under constant perfusion pressure (ca. 120 mm Hg). The steady-state renal extraction ratio of (R)-(+)-DBCA (0.134) was 10 times higher than that of (S)-(-)-DBCA (0.015), indicating high selectivity for (R)-(+)-DBCA. The urinary excretion rate and renal excretory clearance (CLrex) were 4 times larger for (R)-(+)DBCA, and the unbound fraction in the perfusate also was higher for (R)-(+)-DBCA (R/S = 1.58). Fractional excretion (FE) and intrinsic clearance for tubular secretion (CLrsec,int) were about 3 times larger for (R)-(+)-DBCA than the antipode, showing the stereoselectively predominant secretion of (R)-(+)-DBCA. The N-monodemethylated metabolite, M-1, was found only for the R-(+)-enantiomer in the perfusate and urine, revealing highly stereoselective N-monodemethylation in the kidney. The CLrSec,int value for(R)-(+)-M-1 was 2.5 times larger than that for (R)-(+)-DBCA. The perfusion study using each enantiomer decreased RIS ratios of the extraction ratio (9.9), urinary excretion rate (3.9) and excretory clearance (3.9) in the perfusion of the racemate to 3.9, 2.1 and 2.1, respectively. No significant difference was found between (R)-(+)- and (S)-(-)-DBCA in FE and CLrsec,int. The declined stereoselectivity in renal excretion parameters may be due to competitive inhibition of the tubular secretion of (R)-(+)DBCA by the (R)-(+)-M-1 formed which possessed greater secretion ability in the (R)-(+)-DBCA perfusion study, whereas (S)(-)-DBCA was secreted without great inhibition by (S)-(-)-M-1 in the (S)-(-)-DBCA perfusion because of a small amount of generated metabolite. Plotting of FE ratios of DBCA enantiomers to(R)-(+)-M-1 against FE of(R)-(+)-M-1 suggests that the actual FE for (R)-(+)-DBCA was 2 times larger than that for (S)-(-)DBCA, and that (S)-(-)-DBCA secretion was inhibited more easily by (R)-(+)-M-1.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

1. Enantiomer-enantiomer interaction of 5-dimethylsulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA), a uricosuric, diuretic and antihypertensive agent, was studied from the pharmacokinetics of the enantiomers following intravenous injection of individual enantiomers and racemate into male cynomolgus monkeys. Also studied was the involvement of the anion transport system in the renal excretion of DBCA by comparison of the pharmacokinetics in probenecid-treated and non-treated animals.
2. Separate administration of individual enantiomers showed higher plasma concentrations of (S)(-)-DBCA than those of the antipode, at an early period after dosing. Both enantiomers disappeared rapidly from plasma with an elimination half-life (t1/2beta) of 0.35-0.38 h. Unbound fractions were 18.9% for the (R)(+)-enantiomer and 10.2% for the (S)(-)-enantiomer. The major portion of both enantiomers was excreted by 6 h after dosing and 77-78% of the dose was recovered within 48 h, principally as the unchanged drug. Tubular secretion contributed significantly to the renal excretion of DBCA, because tubular secretion clearance values of unbound drug (CL(rf,s)) were 14- to 29-fold greater than creatinine clearance.
3. The presence of the antipode decreased the tubular secretion clearance (CL(rf,s)) value of unbound (S)(-)-enantiomer by 30%; and tended to decrease that for the unbound (R)(+)-enantiomer, although not significantly. This indicates the occurrence of enantiomer-enantiomer interaction in the process of renal tubular secretion, and the inhibition of (S)(-)-DBCA renal excretion in the presence of the antipode.
4. Probenecid treatment significantly decreased the CL(rf,s) of both enantiomers, and the extent of inhibition for the (S)(-)-enantiomer (53%) was significantly higher than that for the antipode (14%). These results show that renal tubular secretion of DBCA involves an anion transport system which prefers the (S((-)-enantiomer, and that probenecid can preferentially inhibit (S)(-)-enantiomer secretion.

DOI： 10.3109/00498259309059393

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHARMACEUTICAL ASSN  

5-Dimethylsulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (DBCA), a promising uricosuric, diuretic, and antihypertensive agent, was administered intravenously to rats. The levels of DBCA in plasma and the areas under the curve of concentration versus time (AUC values) of the S(-)-enantiomer were higher than those of the R(+)-enantiomer. Total body clearance was significantly greater for the R(+)-enantiomer. This stereoselective elimination was due to a difference in the nonrenal clearance, which seemed to reflect hepatic metabolism or biliary excretion. Hepatic metabolism seemed more likely because AUC and the amount of urinary excretion of the N-monodemethylated metabolite of DBCA were greater for the R(+)-enantiomer. The plasma had higher free fractions of the S(-)-enantiomer, a result suggesting that this enantiomer is distributed more readily to the tissues, including the liver. This result indicates that protein binding was not responsible for the stereoselective metabolism of (R)-(+)-DBCA. Although there was no difference in the renal clearances of the enantiomers, the renal clearance of free (R)-(+)-DBCA exceeded that of the S(-)-enantiomer, a result indicating the preferential excretion of the R(+)-enantiomer into the urine. Comparison of the pharmacokinetics of individual enantiomers after intravenous administration of each enantiomer or its racemate showed that the enantiomers interact with one another; dosing with racemate delayed the elimination of each enantiomer because of mutual inhibition of hepatic metabolism and renal excretion for (R)-(+)-DBCA and of renal excretion for (S)-(-)-DBCA.

DOI： 10.1002/jps.2600810919

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILLIAMS & WILKINS  

S-8666 (5-dimethyl-sulfamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid), a novel uricosuric antihypertensive diuretic, and its N-monodemethylated metabolite (M-I) were studied in a single pass perfused rat liver preparation under constant perfusate flow (ca. 16 ml/min). During perfusion with 100 nmol/ml of racemic S-8666 not containing bovine serum albumin (BSA), the steady-state hepatic extraction ratio of R(+)-S-8666 was two times higher (0.65 +/- 0.08) than that of S(-)-S-8666 (0.34 +/- 0.08). R(+)- and S(-)-M-I in the effluent perfusate plasma accounted for 64 and 18% of the influx rate of each enantiomeric S-8666, respectively. The N-monodemethylation was found to be responsible for the hepatic extraction of S-8666 enantiomers. S(-)-S-8666 was excreted into bile at a more rapid rate than the R(+)-enantiomer. Biliary excretion of R(+)-M-I was faster than S(-)-M-I, although the excretion rates of M-I were slower than those of S-8666 for both enantiomers. The steady-state extractions of preformed R(+)- and S(-)-M-I were low and a significant difference [S(-) &gt; R(+)] was observed during the perfusion of 100 nmol/ml preformed racemic M-I without BSA. Increasing the concentration of BSA in the perfusate led to decreases in the extraction ratios of S-8666 enantiomers and biliary excretion rates of all chemicals, which was due to the decreases in the free fractions of S-8666 and M-I enantiomers. The binding of S-8666 and M-I enantiomers to BSA also showed stereoselectivity [R(+) &lt; S(-)]. Although the appearance of M-I enantiomers in the effluent gradually decreased with an increase of the BSA contents in the perfusate, the R(+)- to S(-)-M-I ratio of the outflux rate from the inferior vena cava increased, revealing greater stereoselectivity of S-8666 N-monodemethylation [R(+) &gt; S(-)] with stereoselective binding to BSA.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHARMACEUTICAL ASSN  

DOI： 10.1002/jps.2600790413

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

DOI： 10.1248/bpb1978.13.57

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PLENUM PUBL CORP  

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Authorship：Lead author   Language：English   Publisher：PHARMACEUTICAL SOC JAPAN  

DOI： 10.1248/cpb.36.1214

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/0378-5173(87)90148-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

DOI： 10.1248/cpb.34.3415

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

DOI： 10.1248/bpb1978.9.532

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER/PLENUM PUBLISHERS  

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Language：English   Publisher：Steering committee of symposium on ultrasonic electronics  

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Language：Japanese  

DOI： 10.11522/pscjspe.2010S.0.475.0

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Language：English   Publisher：Steering committee of symposium on ultrasonic electronics  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：TAYLOR & FRANCIS INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：TAYLOR & FRANCIS INC  

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Language：Japanese   Publisher：技術情報協会  

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Language：Japanese   Publisher：日本医療薬学会  

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Language：Japanese   Publisher：日本医療薬学会  

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Language：English  

The clearance of colloidal particles from the blood circulation occurs mainly in the liver, spleen and bone marrow by phagocytes lining blood sinuses in these organs of the reticuloendothelial system (RES). The relative distribution of the injected particles in these organs depends on various factors such as the size, surface properties of the injected particles and also the type of serum proteins adsorbed onto the surface of particles. Proteins that adsorb onto the surface of a particle promoting their phagocytosis are termed opsonins. On the other hand, it has been suggested that certain classes of liposomes and pathogenic microorganisms can attract suppressive substances termed dysopsonins from plasma or serum, thereby minimizing the interaction with phagocytes. From these points of view, it is very important to identify the serum opsonins or dysopsonins and to elucidate the uptake mechanisms of the particulate carrier used for the handling of the in vivo disposition of the drug loaded. We believe that understanding of these regulatory mechanisms may provide an opportunity to target or avoid particulate drug carriers into a specific organ of RES. © 2001, THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM. All rights reserved.

DOI： 10.2745/dds.16.395

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Language：Japanese   Publisher：日本薬物動態学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER PHARMACEUTICAL ASSN  

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Event date： 2022.5.26 - 2022.5.28

Presentation type：Oral presentation (general)  

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Event date： 2022.5.26 - 2022.5.28

Presentation type：Oral presentation (general)  

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Event date： 2021.5.13

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