研究者詳細 - 合葉　哲也

論文 - 合葉　哲也

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Altered Pharmacological Efficacy of Phenobarbital with the Treatment of 7,8-Dihydroxyflavone, an Agonist of Tropomyosin Receptor Kinase B, in Rats 査読

Keiichiro Suzuki, Kazuya Matsumoto, Misa Takenaka, Tetsuya Aiba

Biological and Pharmaceutical Bulletin 46 ( 1 ) 86 - 94 2023年1月

Acute peripheral inflammation increases plasma concentration of hypoglycemic agent nateglinide with decreased hepatic drug-metabolizing activity in rats. 査読

Kojina M, Suzuki K, Nishiwaki A, Aiba T

Biological and Pharmaceutical Bulletin 44 ( 1 ) 96 - 102 2021年1月

Effects of dexamethasone to reverse decreased hepatic midazolam metabolism in rats with acute renal failure. 査読

Doi M, Kajikawa N, Aiba T

Xenobiotica 50 ( 5 ) 506 - 514 2020年3月

In Vivo Study on Mechanism Underlying Increased Pharmacological Effects of Phenobarbital in Rats with Glycerol-Induced Acute Renal Failure 査読

Atsuyoshi Okada, Keiichiro Suzuki, Keisuke Hara, Moeko Kojina, Tetsuya Aiba

Biological and Pharmaceutical Bulletin 42 ( 3 ) 501 - 506 2019年3月

Altered hepatic drug-metabolizing activity in rats suffering from hypoxemia with experimentally induced acute lung impairment 査読

Yuki Hori, Yasumasa Shimizu, Tetsuya Aiba

Xenobiotica 48 ( 6 ) 576 - 583 2018年6月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Taylor and Francis Ltd

1.Hepatic drug-metabolizing activity was investigated in vitro with liver microsomes prepared from rats suffering from hypoxemia with experimentally induced acute lung impairment (ALI). 2.Male Wistar rats received an intrabronchial administration of dilute hydrochloride solution for ALI induction. Pooled liver microsomes were prepared for the normal and ALI rats, and the hepatic drug metabolism mediated by cytochrome P450 (CYP) 3 A was examined in an incubation study with the microsomes. 3.The NADPH-dependent metabolism of midazolam significantly increases in ALI rats as compared with that in normal rats. Testosterone 6β-hydroxylation was also observed to significantly increase in ALI rats. 4.When the hepatic expression of CYP3A proteins was examined, the protein expression of CYP3A1 was shown to significantly increase and that of CYP3A2 remained unaltered in ALI rats. The hepatic expression of NADPH-cytochrome P450 reductase (POR), a protein mediating electron transfer in CYP-mediated drug metabolism, was also revealed to significantly increases in ALI rats. 5.With the findings regarding the midazolam elimination, the hepatic drug-metabolizing activity seems to increase in response to acute hypoxemia, partly due to an altered expression of the CYP3A enzymes, and an augmented electron transfer with an increased POR expression is probably involved in the increase.

DOI： 10.1080/00498254.2017.1349969

Bortezomib combined with standard induction chemotherapy in Japanese children with refractory acute lymphoblastic leukemia 査読

Akihiro Iguchi, Yuko Cho, Minako Sugiyama, Yukayo Terashita, Tadashi Ariga, Yosuke Hosoya, Shinsuke Hirabayashi, Atsushi Manabe, Keisuke Hara, Tetsuya Aiba, Tsugumi Shiokawa, Hiroko Tada, Norihiro Sato

International Journal of Hematology 106 ( 2 ) 291 - 298 2017年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER JAPAN KK

Bortezomib has been shown to be effective and well-tolerated in patients with refractory acute lymphoblastic leukemia (ALL) in the Therapeutic Advances in Childhood Leukemia trial. However, the safety and efficacy of bortezomib have not been evaluated in Japanese pediatric patients. Here, we report the results of a clinical trial designed to evaluate the safety of bortezomib combined with induction chemotherapy in Japanese children with refractory ALL. A total of six patients with B-precursor ALL were enrolled in this study. Four-dose bortezomib (1.3 mg/m(2)/dose) combined with two standard induction chemotherapies was used. Prolonged pancytopenia (grade 4) was observed in all patients. Four of the six patients developed severe infectious complications. Peripheral neuropathy (grade 2) occurred in five patients. The individual plasma bortezomib concentration-time profiles were not related to toxicity and efficacy. Five patients were evaluable for response, and four patients achieved complete response (CR) or CR without platelet recovery (80%). In conclusion, four-dose bortezomib (1.3 mg/m(2)/dose) combined with standard re-induction chemotherapy was associated with a high risk of infectious complications induced by prolonged neutropenia, although high efficacy has been achieved for Japanese pediatric patients with refractory ALL. Attention must be given to severe infectious complications when performing re-induction chemotherapy including bortezomib.

DOI： 10.1007/s12185-017-2235-z

Correlation between the Efficacy of Lamotrigine and the Serum Lamotrigine Level during the Remission Phase of Acute Bipolar II Depression: A Naturalistic and Unblinded Prospective Pilot Study 査読

Akiyoshi Kikkawa, Yoshihisa Kitamura, Tetsuya Aiba, Koichi Hiraki, Toshiaki Sendo

Biological and Pharmaceutical Bulletin 40 ( 4 ) 413 - 418 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

Lamotrigine has acute antidepressant effects in patients with bipolar disorder. However, there is little information regarding appropriate serum levels of lamotrigine and the time until remission after the start of lamotrigine therapy in patients with bipolar II depression. This was a naturalistic and unblinded prospective pilot study. Twelve patients' depressive symptoms were evaluated using the Montgomery-angstrom sberg Depression Rating Scale (MADRS) at the start of treatment and at the time of remission, and blood samples were obtained at the time of remission. Mahalanobis distance was used to analyze the relationship between the MADRS improvement rate and the serum lamotrigine level. Furthermore, we calculated the Spearman's rank correlation coefficient for the relationship between the MADRS improvement rate and the serum lamotrigine level, and produced box plots of the serum lamotrigine level at remission and the time until remission. The Mahalanobis distance for the patient that was co-administered lamotrigine and valproic acid differed significantly from those of the other patients (p<0.001). There was no linear relationship between the serum lamotrigine level and the MADRS improvement rate among the patients that did not receive valproic acid. The median time from the start of lamotrigine therapy until remission was 6 weeks. The serum lamotrigine level does not have an important impact on the acute therapeutic effects of lamotrigine on bipolar II depression. In addition, we consider that different treatment options should be considered for non-responders who do not exhibit any improvement after the administration of lamotrigine for approximately 6 weeks.

DOI： 10.1248/bpb.b16-00725

一般向けビタミン主薬製剤及びビタミン含有保健薬の水溶性ビタミン配合量に基づく類似性分析査読

鈴木啓一郎, 神志那萌子, 合葉哲也

137 ( 5 ) 595 - 602 2017年

Altered hepatic drug metabolizing activity in rats with acute lung impairment

Yuki Hori, Yasumasa Simizu, Tetsuya Aiba

Drug Metabolism Reviews 47 89 - 89 2015年11月

In vivo application of chitosan to improve bioavailability of cyanocobalamin, a form of vitamin B-12, following intraintestinal administration in rats 査読

Yuko Goto, Ayumi Masuda, Tetsuya Aiba

International Journal of Pharmaceutics 483 ( 1-2 ) 250 - 255 2015年4月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

The effect of chitosan on the intestinal absorption of cyanocobalamin (VB12), a stable form of vitamin B-12, was investigated in vivo in rats, with the aim of improving the oral bioavailability of VB12 for anemia treatment in patients with gastrectomy. The bioavailability was evaluated based on the plasma concentration profile of VB12 following intraintestinal administration of the VB12 solution containing chitosan at various concentrations. The bioavailability of VB12 was 0.6 +/- 0.2% when the chitosan-free VB12 solution was administered, while it increased to 10.5 +/- 3.3% when chitosan was dissolved in the VB12 solution at a concentration of 1%. The bioavailability of VB12 increases with the chitosan concentration, in which chitosan seems to augment the amount of VB12 absorbed without affecting the absorption rate constant of VB12. It was also shown that the bioavailability of VB12 does not increase further when the degree of chitosan deacetylation is increased from 83 to 100% by substitutively employing the fully deacetylated chitosan. These findings suggest that the oral administration of VB12 with readily available chitosan may be a practical approach for anemia treatment in patients with gastrectomy. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2015.02.016

Pharmaceutical properties of a low-substituted hydroxypropyl cellulose (L-HPC) hydrogel as a novel external dressing 査読

Atsushi Ogawa, Sachie Nakayama, Mami Uehara, Yasuhiro Mori, Mai Takahashi, Tetsuya Aiba, Yuji Kurosaki

International Journal of Pharmaceutics 477 ( 1-2 ) 546 - 552 2014年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

Controlling the moisture balance between exudates and their transpiration from the surface of wounded skin is important for healing. Low-substituted hydroxypropyl cellulose (L-HPC) hydrogel sheets (HGSs) possessing high water retention and water vapor transmission properties were prepared by neutralizing the highly viscous alkaline liquid of 7-10% L-HPC. Glycerol-impregnated L-HPC hydrogel sheets (L-HPC G-HGSs) were obtained by exchanging aqueous liquid in L-HPC HGSs. The physical characteristics required for wound dressings, i.e., mechanical strength, adhesive strength, and water retention properties, as well as the water vapor transmission (WVT) properties of L-HPC HGSs and L-HPC G-HGSs were evaluated. The mechanical strengths of L-HPC HGSs were enhanced with increases in the L-HPC content. The impregnation of glycerol in L-HPC HGSs yielded a significantly elasticated sheet. The adhesive strengths of L-HPC HGSs were significantly lower than those of commercial medical dressings. Water retention in L-HPC HGSs after being stored for 2 h at 37 degrees C was approximately 50%. The WVT rate of 7% L-HPC HGS was approximately 40 g/m(2)/h, which was markedly higher than that of silicone gel type medical dressings. In conclusion, L-HPC HGSs are promising dressings that maintain an adequate moisture balance by transpiring excessive wound exudates with less damage to the healing wound. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2014.10.043

双極性障害II型患者のうつ状態急性期に対するラモトリギンの血中濃度と効果との関係および寛解までの服用日数に関する検討

吉川明良, 吉川明良, 北村佳久, 合葉哲也, 和田健, 森田幸孝, 岩本崇志, 開浩一, 千堂年昭

臨床薬理 45 ( Supplement ) S250 - S250 2014年11月

Effect of Carrageenan-induced Acute Peripheral Inflammation on the Pharmacokinetics and Hepatic Metabolism of Midazolam in Rats 査読

Noriko Kajikawa, Masami Doi, Jun-ichi Kusaba, Tetsuya Aiba

Drug Metabolism and Pharmacokinetics 29 ( 5 ) 400 - 406 2014年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE SOC STUDY XENOBIOTICS

The effect of carrageenan-induced acute peripheral inflammation (API) on the pharmacokinetics of the hepatically metabolizing compound midazolam (MDZ) was investigated in rats. Rats were subcutaneously treated with lambda-carrageenan in the hind paw to induce API. When MDZ was intravenously administered in male rats, it was demonstrated that the plasma concentration profile of MDZ slightly alters in API rats compared with that in normal rats, while the plasma concentrations of its metabolites, 4-hydroxy and 1'-hydroxy MDZ, are markedly reduced with delayed appearances in API rats. In the incubation study with rat liver microsomes, it was clearly indicated that the generation rates of the two metabolites decrease in API rats. Western blot analysis revealed that hepatic CYP3A1 expression increases, while CYP3A2 expression decreases in API rats. In female rats, in which CYP3A2 is barely expressed in the liver, MDZ metabolism is little affected by API. These findings indicate that the hepatic handling of a therapeutic compound varies with API, largely due to altered hepatic expression of the drug-metabolizing enzyme.

DOI： 10.2133/dmpk.DMPK-14-RG-020

Interspecies comparison of hepatic metabolism of six newly synthesized retinoid X receptor agonistic compounds possessing a 6-[N-ethyl-N-(alkoxyisopropylphenyl)amino]nicotinic acid skeleton in rat and human liver microsomes 査読

Yoshiki Murakami, Yasumasa Shimizu, Akemi Ogasawara, Satoshi Ueshima, Mariko Nakayama, Kohei Kawata, Hiroki Kakuta, Tetsuya Aiba

Drug Development and Industrial Pharmacy 40 ( 8 ) 1065 - 1071 2014年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：INFORMA HEALTHCARE

Objective: The hepatic metabolism of six compounds newly synthesized as retinoid X receptor agonists was characterized in rat and human liver microsomes to examine the relationship between their hepatic metabolism profiles and side chain structures, considering the interspecies difference.
Materials and methods: The compounds used have a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic or 6-[N-ethyl-N-(4-alkoxy-3-isopropylphenyl)amino]nicotinic acid skeleton, in which the isopropoxy, isobutoxy or cyclopropylmethoxy group is employed for the alkoxy group. These compounds were incubated with the microsomes, and their Michaelis-Menten parameters were determined. The incubation study was also performed with various cytochrome P450 (CYP) inhibitors to examine their susceptibilities to the inhibitors. In addition, a molecular docking simulation was conducted to assess the compound's spatial configuration with the CYP isoform when necessary.
Results: The Michaelis-Menten parameters determined are comparable between rats and humans for the compounds having 3-isobutoxy, 4-isobutoxy, 4-isopropoxy and 4-cyclopropylmethoxy groups. However, it was indicated that all compounds except that having the 3-isobutoxy group are metabolized in a different manner between rats and humans. That is, the extent of the contribution of each CYP isozyme is different between those two species. A molecular docking simulation showed that the spatial configuration of the compound to be associated with CYP2D6 markedly changes depending on whether the isobutoxy group is situated at the 3- or 4-position.
Conclusion: A slight difference in the side chain structures markedly alters the compound's metabolic profile, which amplifies the interspecies difference regarding the profile, increasing the difficulty in characterizing the profile in humans with the structural-property relationship and interspecies extrapolation.

DOI： 10.3109/03639045.2013.807278

粉砕法による経管投与における薬剤量損失に対する簡易懸濁法の有用性についての検討

座間味義人, 小山敏広, 合葉哲也, 天野学, 安藤哲信, 倉田なおみ, 名和秀起, 名倉弘哲, 北村佳久, 千堂年昭

静脈経腸栄養 29 ( 4 ) 1027-1033 (J-STAGE) - 1033 2014年7月

記述言語：日本語出版者・発行元：(株)ジェフコーポレーション

【目的】従来の薬剤経管投与法である粉砕法は薬効の減少につながる薬剤量の損失が指摘されている。そこで粉砕法による薬剤量損失に対する簡易懸濁法の有用性について検討した。【方法】頻繁に粉砕指示がなされる5種類の薬剤を用いて粉砕・分包による薬物含量減少、薬剤調製時の懸濁性および実際の経管投与を想定した薬物含量について2つの方法を比較した。【結果】薬剤を粉砕・分包するとそれぞれの薬物含量は減少した。またワーファリン錠を粉砕して水に溶解すると完全には懸濁せず、小さな塊が生じたが、簡易懸濁法では均一に懸濁した。ワーファリン錠の経管投与を想定した実験において粉砕法では薬物含量が大幅に減少したが、簡易懸濁法では、ほとんど損失が認められなかった。【結論】簡易懸濁法は粉砕法に比べて薬剤損失の面で有用性が高いことが示唆され、ワーファリン錠のように安定性が悪い薬剤では特に適正な薬物投与に貢献出来ると考えられる。(著者抄録)

DOI： 10.11244/jjspen.29.1027

Effects of Peritoneal Dialysis on Pharmacotherapy: A Deductive Pharmacokinetic-model Approach to Predict Drug Concentration Profiles in Plasma and Peritoneal Fluid 査読

Mizuki Horiuchi, Soichiro Moriyama, Yukiko Takahata, Tetsuya Aiba, Yuji Kurosaki

Drug Metabolism and Pharmacokinetics 29 ( 2 ) 154 - 161 2014年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPANESE SOC STUDY XENOBIOTICS

The aim of this study was to present a deductive compartment pharmacokinetic (PK) model to predict the concentration profiles of drugs in plasma and peritoneal fluid in peritoneal dialysis (PD) rats. PK parameters of model drugs in normal and experimentally induced acute renal failure (ARF) rats not undergoing PD were obtained inductively in a common regression manner with a two-compartment model. In PD normal and ARF rats, PK parameters relating to the transfer of drugs to the peritoneal dialysate and the progress of renal failure were deductively modified to simulate the drug concentration-time profiles in plasma and in the peritoneal fluid in PD rats. The deductively introduced modifiers were the volume of distribution in the peripheral compartment, plasma protein binding, and solvent movement factor to the peritoneal fluid. Predicted profiles of tolbutamide, propranolol and cefazolin in PD normal and ARF rats were compared with the corresponding observed data. This minimal deductive approach yielded satisfactory accuracy in the prediction of both the plasma and peritoneal fluid concentrations of tolbutamide and propranolol.

DOI： 10.2133/dmpk.DMPK-13-RG-067

双極性障害患者に対するラモトリギンの使用実態調査と考察

Akiyoshi Kikkawa, Yoshihisa Kitamura, Ken Wada, Yukitaka Morita, Takashi Iwamoto, Tetsuya Aiba, Kouiti Hiraki, Toshiaki Sendou

日本病院薬剤師会雑誌 50 ( 4 ) 491 - 494 2014年

遮光器具を用いた光に不安定な薬剤の含量減少の抑制について

座間味義人, 座間味義人, 座間味義人, 東恩納司, 安藤哲信, 武藤浩司, 天野学, 倉田なおみ, 合葉哲也, 北村佳久, 千堂年昭

静脈経腸栄養 29 ( 3 ) SUP54(J-STAGE) 2014年

Effect of Carrageenan-Induced Acute Peripheral Inflammation on the Electrolyte Disposition to Cerebrospinal Fluid in Rats 査読

Kentaro Kono, Atsuyoshi Okada, Atsuko Ishikawa, Tetsuya Aiba

Biological and Pharmaceutical Bulletin 36 ( 11 ) 1829 - 1834 2013年11月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

To clarify whether peripheral inflammation has a remote effect on the central nervous system, the electrolyte disposition between the circulating blood and central nervous system was evaluated in rats with carrageenan-induced acute peripheral inflammation (API). lambda-Carrageenan was subcutaneously injected in the hind paw of the rat, and lithium was utilized as a surrogate marker of sodium. When the plasma and cerebrospinal fluid (CSF) concentrations of lithium were examined following lithium being intravenously administered, it was revealed that the CSF concentration of lithium in API rats is reduced compared to that in normal rats, while the plasma concentration profile of lithium in API rats is indistinguishable from that in normal rats. The pharmacokinetic analysis showed that the lithium disposition from the plasma to CSF markedly decreased by 35.8% in API rats compared to that in normal rats. On the other hand, when lithium was immediately administered into the lateral ventricle, its elimination profiles in CSF were not different between normal and API rats. It is therefore probable that the lithium disposition from the plasma to CSF alters in API rats, reflecting the entry process of electrolytes from the circulating blood to brain tissue being suppressed in response to peripheral inflammation.

DOI： 10.1248/bpb.b13-00531

双極性障害患者に対するラモトリギンの使用実態調査と考察

吉川明良, 北村佳久, 合葉哲也, 和田健, 森田幸孝, 岩本崇志, 開浩一, 千堂年昭

日本医療薬学会年会講演要旨集 23rd 433 - 433 2013年8月

The Effects of Body Weight and Combination Drug Therapy on the Serum Concentrations of Zonisamide in 94 Epileptic dogs: An Epidemiological Analysis 査読

Koya Fukunaga, Tetsuya Aiba, Miyoko Saito, Makoto Muto, Naoyuki Watanabe, Keiko Uchida, Seiichi Okuno, Takayuki Kobayashi, Kensuke Orito

International Journal of Appled Research in Veterinary Medicine 10 ( 3 ) 258 - 263 2012年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：VETERINARY SOLUTIONS LLC

To clarify the effects of background factors such as body weight, combination drug therapy with phenobarbital (PB) and potassium bromide (KBr), age, gender, neuter status, and blood collection time on the serum concentrations of zonisamide (ZNS) in 94 epileptic dogs, serum ZNS concentrations of 141 samples from 94 epileptic dogs were measured by high-performance liquid chromatography with UV detection. Serum ZNS concentrations were divided by the dosage of ZNS, to obtain normalized ZNS concentrations. Multiple linear regression analysis revealed that body weight and combination therapies with KBr, PB, and KBr + PB affected the normalized ZNS concentrations, and normalized ZNS concentrations were positively correlated with body weight. The normalized ZNS concentrations in dogs with PB combination therapy were lower when compared with those concentrations in dogs receiving ZNS alone, but were higher in dogs receiving KBr combination therapy. These results suggest that serum ZNS concentrations are influenced by body weight and combination drug therapies using KBr, PB, and KBr + PB. This information of ZNS characteristics may be useful in determining the initial and modified doses of ZNS in the therapy of epileptic dogs.

In Vivo Application of Chitosan to Facilitate Intestinal Acyclovir Absorption in Rats 査読

Ayumi Masuda, Yuko Goto, Yuji Kurosaki, Tetsuya Aiba

Journal of Pharmaceutical Sciences 101 ( 7 ) 2449 - 2456 2012年7月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

The effect of chitosan on the intestinal absorption of acyclovir (ACV) was evaluated in rats, and factors influencing its facilitative effect on the ACV absorption were examined. When ACV solution containing 1% chitosan with an average molecular weight of 150 kDa was administered into the upper jejunum, a significant increase in the plasma ACV concentration was observed, with the peak ACV concentration being eight times greater than that observed with the chitosan-free solution. The chitosan-free ACV solution, whose viscosity was adjusted to remain unchanged with polyethylene glycol, did not cause an increase in the plasma concentration, and neither did the chitosan-free solutions substitutionally containing low molecular cationic compounds, triethanolamine and kanamycin. When chitosan was digested with chitosanase to shorten its polycationic polysaccharide structure, chitosan subjected to 150-min digestion retained its facilitative effect on ACV absorption, but that subjected to 420-min digestion no longer caused facilitation, in which its average molecular weight was reduced to around 10 kDa. It is therefore indicated that intestinal ACV absorption can be facilitated with chitosan, and that it is necessary for chitosan to have a certain length of polycationic polysaccharide structure to exert such facilitation. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2449-2456, 2012

DOI： 10.1002/jps.23170

Microdialysis法を用いた薬物の筋肉内局所動態評価局所冷却による局所薬物利用率の増大

牧之段敬一, 東恩納司, 崎山達矢, 合葉哲也, 黒崎勇二

日本DDS学会学術集会プログラム予稿集 28回 122 - 122 2012年6月

新規RXRアゴニスト及びその類縁化合物のヒト肝における代謝特性の予測

合葉哲也, 村上由樹, 清水康正, 川田浩平, 中山真理子, 小笠原明美, 岡田淳芳, 黒崎勇二, 加来田博貴

日本薬学会年会要旨集 132年会 ( 2 ) 269 - 269 2012年3月

Comparative study on altered hepatic metabolism of CYP3A substrates in rats with glycerol-induced acute renal failure 査読

Jun-ichi Kusaba, Noriko Kajikawa, Hiromu Kawasaki, Yuji Kurosaki, Tetsuya Aiba

Biopharmaceutics and Drug Disposition 33 ( 1 ) 22 - 29 2012年1月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol-induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis-Menten parameters, Km and Vmax, were examined in the incubation study, the Km values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The Vmax values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased Km values accompanied the decreased Vmax values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the Km value was observed in ARF rats, but it did not accompany the decrease in the Vmax value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti-CYP3A1 and anti-CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats. Copyright (C) 2012 John Wiley & Sons, Ltd.

DOI： 10.1002/bdd.1774

肺移植患者におけるシクロスポリン経口クリアランスに及ぼす移植後経過日数の影響

土井原夕貴, 上島智, 合葉哲也, 佐藤智昭, 河崎陽一, 山根正修, 大藤剛宏, 松永尚, 黒崎勇二, 三好新一郎, 千堂年昭

臨床薬理 42 ( Suppl. ) S268 - S268 2011年10月

P-0589 経腸栄養剤を用いた疎水性薬剤の簡易懸濁法適用の検討(一般演題ポスター発表,医薬品情報・データベース,Enjoy Pharmacists' Lifestyles)

座間味義人, 松永康臣, 合葉哲也, 天野学, 小山敏広, 四宮一昭, 北村佳久, 黒崎勇二, 佐々木健二, 野田真吾, 千堂年昭, 川崎博己, 五味田裕

日本医療薬学会年会講演要旨集 21 280 - 280 2011年9月

Pharmacodynamic Characterization of Nitric Oxide-Mediated Vasodilatory Activity in Isolated Perfused Rat Mesenteric Artery Bed 査読

Shinsuke Inoue, Tetsuya Aiba, Yasuyuki Masaoka, Keiko Shimizu, Yukiko Komori, Mitsunobu Mio, Shingo Takatori, Hiromu Kawasaki, Yuji Kurosaki

Biological and Pharmaceutical Bulletin 34 ( 9 ) 1487 - 1492 2011年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

Vasodilation profiles following a short-term infusion of nitric oxide (NO), acetylcholine (ACh), and sodium nitroprusside (SNP) into an isolated perfused mesenteric artery bed were analyzed in rats to examine their vasodilatory efficacy under physiological conditions. These compounds commonly increase the intracellular NO concentration to exert vasodilatory activity. In an experiment with exogenous NO infusion where 100 mu l of 1 : 300 diluted NO-saturated solution (approx. 53 pmol of NO) was applied, the infusion caused transient vasodilation in a dose-dependent manner, with the peak vasodilation value being 74.7% of the maximum relaxation value. In experiments with ACh, the peak vasodilation value was 81.5% of the maximum at a dose of 60 pawl. The vasodilation profile of ACh was similar to that of NO infusion, but the ACh-induced vasodilation reduced at a slower rate than that induced by NO infusion. The vasodilatory activity of SNP was less potent than that of ACh, and its peak value was 62.8% of the maximum at a dose of 2000 pmol. However, SNP activity was augmented by removing the vascular endothelia of the mesenteric artery bed, and the peak value reached 67.3% of the maximum at a dose of 60 pmol. Pharmacodynamic analysis indicated that NO and ACh are equivalent regarding their vasodilator), efficacy, while the efficacy of SNP was less than 1% of theirs, as the arterial vascular endothelium impeded intracellular SNP-related NO generation, by which 95% of SNP's vasodilator), efficacy was negated. These findings will be helpful to understand factors influencing the therapeutic efficacy of vasodilators.

DOI： 10.1248/bpb.34.1487

Pharmacokinetic properties of newly synthesized retinoid X receptor agonists possessing a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton in rats 査読

Akemi Ogasawara, Yoshiki Murakami, Nobumasa Yakushiji, Fuminori Ohsawa, Jun-ichi Kusaba, Tetsuya Aiba, Yuji Kurosaki, Hiroki Kakuta

Drug Development and Industrial Pharmacy 37 ( 9 ) 1060 - 1067 2011年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：INFORMA HEALTHCARE

Objective: The pharmacokinetic properties of three newly synthesized retinoid X receptor (RXR) agonists were evaluated in rats to elucidate the structural factor influencing their pharmacokinetic properties. Material and methods: Three RXR agonists possessing a common 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton and side chain structures that are slightly different from each other were prepared as we previously reported (Takamatsu et al., ChemMedChem, 2008; 3: 780-787). The plasma concentration profiles of these compounds were evaluated following the intravenous and intra-intestinal administrations. Their hepatic metabolism was characterized using rat liver microsomes. Results: Based on the plasma concentration profile, NEt-3IP (3-isopropoxy) was shown to have a distribution volume of 4.53 L/kg, and to be cleared from the body with an elimination half-time of 0.95 h. The bioavailability of NEt-3IP is 16.4%, whereas those of the isobutoxy analog NEt-3IB and the cyclopropylmethoxy analog NEt-3cPM are 46.5% and 22.6%, respectively. Subsequently, in the experiments using rat liver microsomes, the K-m and V-max values of NEt-3IP were determined as 7.85 mu M and 0.48 nmol/min/mg protein, respectively. This K-m value is nearly the same as those of NEt-3IB and NEt-3cPM, but the V-max value is noticeably smaller. Additionally, it was revealed that the CYP family mainly metabolizing NEt-3IP is different from those metabolizing the other analogs. Conclusion: Based on these findings, the pharmacokinetic properties of the compounds possessing this type of the skeleton seem to be largely influenced by a slight modification of the side chain structure.

DOI： 10.3109/03639045.2011.559247

肺移植患者におけるタクロリムス血中濃度推移の母集団解析

上島智, 合葉哲也, 佐藤智昭, 河崎陽一, 山根正修, 大藤剛宏, 松永尚, 黒崎勇二, 三好新一郎, 千堂年昭

TDM研究 28 ( 3 ) s180 - s180 2011年6月

薬物の筋肉内拡散・分布動態に及ぼす血流量の影響局所冷却時の動態特性

牧之段敬一, 東恩納司, 村上仁美, 合葉哲也, 黒崎勇二

日本薬剤学会年会講演要旨集 26年会 141 - 141 2011年5月

Empirical Approach for Improved Estimation of Unbound Serum Concentrations of Valproic Acid in Epileptic Infants by Considering Their Physical Development 査読

Satoshi Ueshima, Tetsuya Aiba, Tomoaki Sato, Hisashi Matsunaga, Yuji Kurosaki, Yoko Ohtsuka, Toshiaki Sendo

Biological and Pharmaceutical Bulletin 34 ( 1 ) 108 - 113 2011年1月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The unbound serum concentration of valproic acid (VPA) is closely related to its therapeutic efficacy. In epileptic infants, the unbound VPA concentration varies largely from patient to patient, being difficult to predict using the reported equations for older children. To establish an equation to estimate the unbound concentration in infants, we empirically characterized the relationship between total and unbound VPA concentrations, taking their growth and development into consideration. Data were retrospectively collected from archived clinical records of 30 epileptic infants aged 0-11 months old. The relationship between total and unbound VPA concentrations was analyzed according to the Langmuir equation, in which the patient's body weight, height, and body surface area were considered as physical development indices. Inter- and intra-individual variabilities in the VPA concentrations were also considered. It was shown that the unbound VPA concentration in infants is properly estimated when their body weights are taken into account, in which the parameter for the maximum binding site concentration (Bm) increases as the body weight increases, while that for the dissociation constant (Xd) is unaltered. Additionally, the relationship was shown to slightly change when the infants are concomitantly treated with VPA and the other antiepileptics. These findings provide useful information to adjust the VPA dosage to achieve optimal therapeutic efficacy in epileptic infants.

DOI： 10.1248/bpb.34.108

いま求められる薬剤師の教育力

調剤と情報 17 ( 1 ) 17 - 18 2011年

ジェネリック医薬品使用・銘柄変更ガイダンス（第二版）査読

合葉哲也, 出石啓治, 飯島康典, 岩月進, 加藤久幸, 小林大高, 坂巻弘之

日本薬剤師会雑誌 63 ( 8 ) 947 - 953 2011年

Altered Electrolyte Handling of the Choroid Plexus in Rats with Glycerol-induced Acute Renal Failure 査読

Atsuko Ishikawa, Kentaro Kono, Rie Sakae, Tetsuya Aiba, Hiromu Kawasaki, Yuji Kurosaki

Biopharmaceutics and Drug Disposition 31 ( 8-9 ) 455 - 463 2010年11月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY

The altered electrolyte handling of the choroid plexus was investigated in rats with acute renal failure (ARF) using lithium and rubidium as surrogate markers for sodium and potassium, respectively. Firstly, the transport of these two markers from the plasma to cerebrospinal fluid (CSF) was evaluated after they were concurrently injected into the femoral vein. As a result, their disposition from the plasma to CSF was shown to decrease in ARF rats, but the relationship profile between those two markers was not different from that observed in normal rats, indicating that the decreased disposition of lithium and rubidium occurs without affecting the stoichiometric balance. To clarify the mechanisms accounting for the decreased disposition, an inhibition study was then performed. When bumetanide, an inhibitor of the Na+/K+/2Cl(-) co-transporter, was directly introduced into the cerebroventricle prior to lithium and rubidium being intravenously administered, a marked increase in the markers' disposition was observed. However, such an increased disposition did not occur when bumetanide was injected into the femoral vein. Other inhibitors, such as amiloride for the Na+/H+ exchanger and ouabain for Na+/K+-ATPase, did not show any effects on marker disposition regardless of the inhibitor being administered into either the cerebroventricle or femoral vein. These findings suggest that the decreased marker disposition in ARF rats is due to an increased efflux process of the choroid plexus mediated by the Na+/K+/2Cl(-) co-transporter. That is, electrolyte efflux from the CSF to plasma increases, and thereby the electrolyte influx from the plasma to CSF is counteracted. Copyright (C) 2010 John Wiley & Sons, Ltd.

DOI： 10.1002/bdd.726

小児におけるテイコプラニンの母集団薬物動態解析血中濃度に及ぼす基礎疾患の影響

槇田崇志, 上島智, 佐藤智昭, 合葉哲也, 黒崎勇二, 松永尚, 千堂年昭

TDM研究 27 ( 3 ) s155 - s155 2010年6月

小児てんかん患者を対象としたバルプロ酸血中遊離型濃度の予測精度評価

小松仁美, 上島智, 佐藤智昭, 松永尚, 合葉哲也, 黒崎勇二, 大塚頌子, 千堂年昭

TDM研究 27 ( 3 ) s191 - s191 2010年6月

簡易懸濁用容器「けんだくん」を用いた光に不安定な薬剤の含量減少の抑制について

座間味義人, 東恩納司, 安藤哲信, 武藤浩司, 天野学, 倉田なおみ, 合葉哲也, 北村佳久, 松永尚, 千堂年昭, 黒崎勇二, 佐々木健二, 川崎博己, 五味田裕

日本薬学会年会要旨集 130th ( 4 ) 284 - 284 2010年3月

血管平滑筋弛緩作用の薬力学モデル解析

合葉哲也, 井上真輔, 正岡康幸, 清水けい子, 小森有希子, 高取真吾, 見尾光康, 川崎博己, 黒崎勇二

日本薬学会年会要旨集 130年会 ( 4 ) 265 - 265 2010年3月

新規骨格を有するRXRアゴニストの体内動態に関する基礎的検討

村上由樹, 小笠原明美, 大澤史宜, 合葉哲也, 川崎博己, 加来田博貴, 黒崎勇二

日本薬学会年会要旨集 130年会 ( 4 ) 265 - 265 2010年3月

Population Pharmacokinetic Analysis of Vancomycin Using Serum Cystatin C as a Marker of Renal Function 査読

Akihiro Tanaka, Tetsuya Aiba, Takashi Otsuka, Katsuya Suemaru, Tatsuya Nishimiya, Tomoyoshi Inoue, Mitsuharu Murase, Yuji Kurosaki, Hiroaki Araki

Antimicrobial Agents and Chemotherapy 54 ( 2 ) 778 - 782 2010年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC MICROBIOLOGY

We determined the population pharmacokinetics of vancomycin (VAN) using the glomerular filtration rate (GFR) estimated from the serum cystatin C concentration. We examined the predictive performance of the trough serum VAN concentration for determination of the initial dose by using a new model for the analysis of the population pharmacokinetic parameters. Data for 86 patients were used to estimate the values of the population pharmacokinetic parameters. Analysis with a nonlinear mixed-effects modeling program was done by using a one-compartment model. Data for 78 patients were used to evaluate the predictive performance of the new model for the analysis of population pharmacokinetic parameters. The estimated GFR values determined by using Hoek's formula correlated linearly with VAN clearance (VAN clearance [ml/min] = 0.825 x GFR). The mean volume of distribution was 0.864 (liters/kg). The interindividual variability of VAN clearance was 19.8%. The accuracy of the prediction determined by use of the new model was statistically better than that determined by use of the Japanese nomogram-based model because the 95% confidence interval (-3.45 to -1.38) of the difference in each value of the mean absolute error (-2.41) did not include 0. Use of the serum cystatin C concentration as a marker of renal function for prediction of serum VAN concentrations may be useful.

DOI： 10.1128/AAC.00661-09

乳児を対象としたバルプロ酸血中遊離型濃度の母集団解析

上島智, 合葉哲也, 佐藤智昭, 松永尚, 黒崎勇二, 大塚頌子, 千堂年昭

臨床薬理 40 ( Suppl. ) S242 - S242 2009年11月

ヨード造影剤と相互作用を有する薬剤に対するリスクマネジメント

清水けい子, 勝部理早, 岡崎宏美, 千堂年昭, 合葉哲也, 黒崎勇二

日本医療薬学会年会講演要旨集 19 304 - 304 2009年9月

Poor applicability of estimation method for adults to calculate unbound serum concentrations of valproic acid in epileptic neonates and infants 査読

S. Ueshima, T. Aiba, N. Ishikawa, T. Sato, H. Kawasaki, Y. Kurosaki, Y. Ohtsuka, T. Sendo

Journal of Clinical Pharmacy and Therapeutics 34 ( 4 ) 415 - 422 2009年8月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC

Objective:
To characterize the relationship between total and unbound concentrations of valproic acid (VPA) in epileptic neonates and infants, the clinical examination records of those patients archived via therapeutic drug monitoring (TDM) activities were retrospectively analyzed.
Methods:
The screening encompassed 249 records of 114 epileptic patients aged 0-19 years old, who were treated with VPA monotherapy and whose total and unbound VPA concentrations were determined. These data were divided into groups according to the patients' age. In each group, the relationship between total and unbound VPA concentrations was compared to a reference profile, and the deviation from the reference was evaluated. The reference profile was calculated using the Langmuir equation, in which two parameters Kd and Bm were set to 7 center dot 8 and 130 mu g/mL, respectively, according to our previous findings.
Results:
The relationship between total and unbound VPA concentrations of patients of 0 years old considerably deviated from the reference, and their unbound VPA concentrations were generally higher compared to the corresponding reference values. It is suggested that the large deviation is related to the fact that the serum albumin concentrations of patients younger than 1 year old tend to be lower than those of patients in other age groups.
Conclusion:
Since the relationship between the VPA concentrations of epileptic neonates and infants is noticeably different from the reference, the unbound serum VPA concentrations of these patients are not adequately estimated using the same method as that for grown-ups. The unbound VPA concentrations of neonates and infants should be explicitly determined via TDM activities.

DOI： 10.1111/j.1365-2710.2009.01022.x

乳児を対象としたバルプロ酸血中遊離型濃度の高精度推定式の構築

上島智, 合葉哲也, 佐藤智昭, 川崎博己, 黒崎勇二, 大塚頌子, 松永尚, 千堂年昭

TDM研究 26 ( 3 ) s161 - s161 2009年6月

新規レチノイドX受容体アゴニストNEt-3IPのラットにおける体内動態評価

小笠原明美, 薬師寺信匡, 合葉哲也, 川崎博己, 黒崎勇二, 加来田博貴

日本薬学会年会要旨集 129年会 ( 4 ) 220 - 220 2009年3月

Efficacy of Peritoneal Dialysis of Tolbutamide in Rats Under Conditions of the Plasma Unbound Fraction Being Increased 査読

Takashi Makita, Tetsuya Aiba, Yuki Izuwa, Yukiko Komori, Hiromu Kawasaki, Yuji Kurosaki

Biopharmacutics and Drug Disposition 30 ( 1 ) 1 - 8 2009年1月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOHN WILEY & SONS LTD

Peritoneal dialysis of a highly protein-bound compound, tolbutamide, was examined in rats to clarify whether the efficacy of the peritoneal dialysis of such compounds increases proportionally as their unbound fractions increase. As expected, it was shown that the tolbutamide concentration of the peritoneal dialysate rose as the unbound fraction of tolbutamide increased. However, the efficacy of peritoneal dialysis of tolbutamide was proportionally elevated only when the unbound fraction was slightly increased by sulfa methoxazol e treatment. When the unbound fraction of tolbutamide was increased 7.8 times by sulfa dimethoxin e treatment, the dialysis efficacy was increased to only 58% of that expected. This discrepancy between the observed and expected values regarding dialysis efficacy was more marked when experiments were performed in rats with experimentally induced acute renal failure. Pharmacokinetic analysis indicated that the intrinsic dialysis clearance of tolbutamide decreased when its unbound fraction was greatly increased. These findings suggest that peritoneal dialysis may be mediated not only by passive diffusion, but also by concentration-dependent processes. The efficacy of the peritoneal dialysis of therapeutic compounds may be overestimated if the estimation is based only on their unbound fraction measured under control conditions. Copyright (C) 2009 John Wiley & Sons, Ltd.

DOI： 10.1002/bdd.640

Comparative Study of Increased Plasma Quinidine Concentration in Rats with Glycerol- and Cisplatin-induced Acute Renal Failure 査読

Yuki Izuwa, Jun-ichi Kusaba, Mizuki Horiuchi, Tetsuya Aiba, Hiromu Kawasaki, Yuji Kurosaki

Drug Metabolism and Pharmacokinetics 24 ( 5 ) 451 - 457 2009年

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAP SOC STUDY XENOBIOTICS

A comparative study of altered plasma concentration of quinidine in rats with glycerol- and cisplatin-induced acute renal failure (ARF) was conducted with quinidine used as a positively charged and liver-metabolized therapeutic compound. Although apparent total body clearance of quinidine decreased to 68 and 48% of the normal value in glycerol- and cisplatin-induced ARF rats, respectively, its distribution decreased only in glycerol-induced ARF rats. The plasma unbound fraction of quinidine decreased in glycerol-induced ARF rats, which was not observed in cisplatin-induced ARF rats. The plasma level of alpha(1)-acid glycoprotein (AGP) increased in glycerol-induced ARF, but not in cisplatin-induced ARF rats. It is therefore conceivable that the plasma concentration of positively charged and liver-metabolized compounds generally increases due to hepatic elimination suppressed as renal function decreases, but the pharmacokinetic impact of suppressed hepatic elimination is occasionally difficult to observe in some ARF model rats since it may be blurred by the influence of increased plasma AGP level.

DOI： 10.2133/dmpk.24.451

Decreased lithium disposition to cerebrospinal fluid in rats with glycerol-induced acute renal failure 査読

Rie Sakae, Atsuko Ishikawa, Tomoko Niso, Yukiko Komori, Tetsuya Aiba, Hiromu Kawasaki, Yuji Kurosaki

Pharmaceutical Research 25 ( 10 ) 2243 - 2249 2008年10月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER/PLENUM PUBLISHERS

Purpose. The lithium disposition to cerebrospinal fluid (CSF) was evaluated in rats with acute renal failure (ARF) to examine whether electrolyte homeostasis of the CSF is perturbed by kidney dysfunction. In addition, the effects of renal failure on choroid plexial expressions of the Na+-K+-2Cl(-) co-transporter (NKCC1) and Na+/H+ exchanger (NHE1) were also studied.
Methods. After lithium was intravenously administered at a dose of 4 mmol/kg, its concentration profile in plasma was evaluated by collecting plasma specimens, while that in CSF was monitored with a microdialysis probe in the lateral ventricles. NKCC1 and NHE1 expressions were measured via the Western immunoblot method using membrane specimens prepared from the choroid plexus in normal and ARF rats.
Results. The lithium concentration in CSF of ARF rats was 30% lower than that of normal rats, while their plasma lithium profiles were almost the same, indicating that the lithium disposition to CSF was decreased in ARF rats. It was revealed that the choroid plexial expression of NKCC1 was increased by 40% in ARF rats, but that of NHE1 was unchanged.
Conclusion. ARF decreases the lithium disposition to CSF, possibly by promoting lithium efflux from CSF due to increased NKCC1 expression in the choroid plexus.

DOI： 10.1007/s11095-008-9612-5

Frequency of decreased renal function between patients treated with brand and generic products of vancomycin hydrochloride injection 査読

Yuki Izuwa, Satoshi Ueshima, Tomoaki Sato, Masatoshi Okazaki, Tetsuya Aiba, Hiromu Kawasaki, Yuji Kurosaki, Toshiaki Sendo

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 128 ( 10 ) 1493 - 1498 2008年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The frequency of decreased renal function was compared between patients treated with brand and generic products of vancomycin injection (VCM) in a retrospective manner based on the clinical examination records archived in Okayama University Hospital. A total of 122 patients were found to have been solely treated with vancomycin injection for MRSA infection, and their examination records were analyzed. The renal function of those patients was evaluated based on the serum creatinine concentration (SCr), and patients whose SCr was maximally elevated above the defined upper limit of the normal range (1.20 mg/dl for mates and 0.96 mg/dl for females) were considered to show decreased renal function. Although the amount of VCM administered to patients was larger in the case of generic rather than brand products, the percentage of patients whose renal function was decreased during VCM treatment was not significantly different between the VCM products, in which 2 among 62 patients receiving the brand product and 4 among 60 receiving the generic product were reported to show decreased renal function. It was additionally revealed that 3 of those 4 patients with a decreased renal function related to the generic product were not treated as instructed by the package insert, and their trough VCM concentration exceeded the recommended level of 10 mu g/ml. With these findings, the brand and generic VCM products are considered to be similar regarding the adverse effect of decreasing renal function.

岡山大学薬学部におけるPBL導入の現状と6年制に向けての課題

岡崎宏美, 四宮一昭, 名倉弘哲, 北村佳久, 合葉哲也, 高山房子, 黒崎勇二, 川崎博己, 千堂年昭

医療薬学フォーラム講演要旨集 16th 304 2008年7月

ロバスト回帰を用いる難治性ネフローゼ患者におけるシクロスポリンのAUC推定方法に関する検討

上島智, 合葉哲也, 佐藤智昭, 黒崎勇二, 瀧上慶一, 杉山斉, 槇野博史, 千堂年昭

TDM研究 25 ( 3 ) s182 - s182 2008年6月

塩酸バンコマイシンの先発医薬品と後発医薬品における腎障害発現状況の比較検討

出羽祐基, 上島智, 佐藤智昭, 岡崎昌利, 合葉哲也, 川崎博己, 黒崎勇二, 千堂年昭

日本薬学会年会要旨集 128年会 ( 4 ) 168 - 168 2008年3月

Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children 査読

S. Ueshima, T. Aiba, T. Makita, S. Nishihara, Y. Kitamura, Y. Kurosaki, H. Kawasaki, T. Sendo, Y. Ohtsuka, Y. Gomita

Journal of Clinical Pharmacy and Therapeutics 33 ( 1 ) 31 - 38 2008年2月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BLACKWELL PUBLISHING

Objective: To establish a regression equation to properly estimate the unbound serum concentration of valproic acid (VPA) from its total serum concentration; the relationship between total and unbound serum VPA concentrations was retrospectively characterized.
Methods: Data were obtained from the clinical examination records that were routinely archived during therapeutic drug monitoring. The screening encompassed 342 records of 108 paediatric patients whose total and unbound VPA concentrations had been determined. The relationship between total and unbound VPA concentrations was characterized according to the Langmuir equation by taking account of inter-individual variability with the NONMEM program.
Results: The total VPA concentration (C-t) in the screened patients ranged from 5.5 to 179.8 mu g/mL, and the unbound VPA concentration (C-f) increased in a non-linear manner as the total VPA concentration increased. Taking account of the effects of antiepileptics concurrently administered, the VPA dissociation constant (K-d) and maximum binding site concentration (B-m) were 7.8 +/- 0.7 and 130 +/- 4.5 mu g/mL respectively, for the regression equation, C-t = C-f + B-m.C-f/(K-d + C-f). An alteration in the unbound concentration was seen in patients who were treated with the combination of VPA and ethosuximide and in those who received two additional antiepileptics.
Conclusions: A regression equation for estimation of the unbound VPA concentration, based on total VPA concentration collected during routine therapeutic drug monitoring was established. Use of two additional antiepileptics and ethosuximide treatment was considered as potential factors affecting unbound VPA concentration.

DOI： 10.1111/j.1365-2710.2008.00885.x

Individualized dosage adjustment of valproic acid based on unbound serum concentration in intractable epileptic children 査読

Ueshima Satoshi, Aiba Tetsuya, Sato Tomoaki, Kawasaki Hiromu, Kurosaki Yuji, Ohtsuka Yoko, Sendo Toshiaki

YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN 128 92 2008年

Application of the correlation of in vitro dissolution behavior and in vivo plasma concentration profile (IVIVC) for soft-gel capsules - a pointless pursuit? 査読

Hidekatsu Nishimura, Chlaki Hayashi, Tetsuya Aiba, Ichiro Okamoto, Yuji Miyamoto, Susumu Nakade, Kazuhisa Takeda, Yuji Kurosaki

Biological and Pharmaceutical Bulletin 30 ( 11 ) 2221 - 2225 2007年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

Plasma concentration profiles of arundic acid ((R)-(-)-2-propyloctanoic acid), an oil-like medicine, administered as soft-gel capsules in human clinical tests were predicted from the dissolution test data of the soft-gel capsules with different storage terms (short- and long-term stored drugs) by applying the in vitro-in vivo correlation (IVIVC). We established two linear-regression IVIVCs, which were characterized by either the in vitro dissolution behaviors against the pH 8.0 dissolution medium or the pH 6.8 dissolution medium containing 2% sodium dodecyl sulfate (SDS), in this study. Also, the prediction accuracies for the in vivo plasma profiles in humans for these two IVIVCs were compared. Regarding dissolution from the long-term stored capsule in pH 8.0 dissolution medium without surfactant, the prediction accuracies of the in vivo plasma profiles in humans were not satisfactory for the obtained IVIVC. The use of pH 6.8 dissolution medium containing 2% SDS, according to the Japanese guideline, improved the dissolution of the long-term stored capsule. Furthermore, the prediction accuracies for the in vivo plasma profiles in humans for these two IVIVCs were compared. The IVIVC established by the in vitro dissolution data obtained with the dissolution medium containing surfactant more effectively predicted the plasma drug concentration profiles following oral administrations of the soft-gel capsules under both storage conditions.

DOI： 10.1248/bpb.30.2221

乳幼児における血中遊離形バルプロ酸濃度の遡及的解析

合葉哲也, 上島智, 石川七瀬, 佐藤智昭, 川崎博己, 黒崎勇二, 大塚頌子, 千堂年昭

臨床薬理 38 ( Suppl. ) S237 - S237 2007年11月

Evaluation of intramuscular lateral distribution profile of topically administered acetaminophen in rats 査読

Yuji Kurosaki, Masahiro Tagawa, Akiho Omoto, Hiroshi Suito, Yukiko Komori, Hiromu Kawasaki, Tetsuya Aiba

International Journal of Pharmacetics 343 ( 1-2 ) 190 - 195 2007年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

To clarify to what extent topically administered drug molecules horizontally permeate into tissues surrounding the administration site, the intramuscular lateral concentration profile of acetaminophen was investigated in vivo using the microdialysis method in rats. When acetaminophen was intramuscularly administered for 6 h in a pinpoint manner at a constant rate of 3 mu g/min, it was clearly detected in the muscle surrounding the administration site, being 17.5 mu g/ml when measured at a 2 mm distance from the administration site. The concentration in the muscle was decreased as the distance increased, and those measured at 5 mm and 40 rum were 0.35 mu g/ml and 0.09 mu g/ml, respectively. In addition, it was shown that the concentration in the muscle at 40 turn reflected the compound's concentration in plasma, but not the compound's horizontal permeation from the administration site. With these observations, the intramuscular distribution profile of acetaminophen was numerically characterized according to Fick's law. As a result, it was revealed that horizontal permeation is the primary process accountable for the increased intramuscular concentration only in the area adjacent to the administration site, and the radius of the adjacent area was calculated to be 5.80 turn for acetaminophen. (C) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2007.05.020

てんかん患児における遊離形バルプロ酸濃度に及ぼす併用薬の影響

上島智, 合葉哲也, 佐藤智昭, 川崎博己, 黒崎勇二, 千堂年昭

TDM研究 24 ( 3 ) s153 - s153 2007年7月

Alteration of therapeutic efficacy of lipid microspheres incorporating prostaglandin E-1 by mixing with aqueous solution 査読

Yukiko Komori, Tetsuya Aiba, Miki Kushima, Hiromu Kawasaki, Yuji Kurosaki

Journal of Pharmaceutical Sciences 96 ( 4 ) 935 - 943 2007年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOHN WILEY & SONS INC

To clarify whether the therapeutic efficacy of lipid microspheres incorporating prostaglandin E-1 (lipo-PGE(1)) is altered when mixed and coinfused with clinical solutions, the original lipo-PGE(1) solution (20 mu g/mL) was mixed with three clinical infusion solutions: 0.9% sodium chloride solution, Hartmann's solution, and fat emulsion for parenteral nutrition. These diluted lipo-PGE(1) (2 mu g/mL) solutions were administered to rats, and their hemodynamic and antiplatelet effects were examined. Peripheral blood flow was increased by 76 +/- 4% from the control level when the lipo-PGE(1) solution diluted with the fat emulsion was administered, while it was increased by 43 +/- 6% and 36 +/- 17%, respectively, when the lipo-PGE(1) solutions diluted with 0.9% sodium chloride and Hartmann's solution were administered. As for the antiplatelet effects of the lipo-PGE(1) solutions, the progression of digit gangrene in thromboangiitis obliterans (TAO) rats was significantly suppressed by the administration of lipo-PGE(1) solution diluted with the fat emulsion, but it was not suppressed by lipo-PGE(1) solution diluted with 0.9% sodium chloride. These findings indicate that the therapeutic efficacy of lipo-PGE(1) is decreased when it is mixed with an aqueous solution such as 0.9% sodium chloride.

DOI： 10.1002/jps.20790

Effects of capsaicin on intestinal cephalexin absorption in rats 査読

Yukiko Komori, Tetsuya Aiba, Risa Sugiyama, Chie Nakai, Hiromu Kawasaki, Yuji Kurosaki

Biological and Pharmaceutical Bulletin 30 ( 3 ) 547 - 551 2007年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The effects of capsaicin on intestinal cephalexin absorption were investigated by means of in situ single pass perfusion in rats to clarify whether this pungent compound present in spice is a potential factor altering the intestinal drug absorption processes. Under the control condition, cephalexin was absorbed at a rate of 1.16 +/- 0.08 and 0.90 +/- 0.06 nmol/min/cm in the jejunum and ileum, respectively. The intestinal cephalexin absorption rate was decreased when capsaicin was dissolved in the perfusate at a concentration of 400 mu m, being 0.54 +/- 0.07 and 0.46 +/- 0.10 nmol/min/cm in the jejunum and ileum, respectively. The inhibitive effect of capsaicin on intestical cephalexin absorption was diminished when ruthenium red, a non-selective inhibitor of the transient receptor potential (TRP) cation channels, was intravenously infused into the rat during the experiment. Moreover, when we evaluated the paracellular permeability of cephalexin by utilizing a competitive inhibitor, glycylsarcosine, it was demonstrated that glycylsarcosine-insensitive intestinal cephalexin absorption in the jejunum was increased by 4.5 times in the presence of 400 mu m capsaicin. These findings indicate that capsaicin affects both transcellular and paracellular pathways of intestinal cephalexin absorption by interacting with the I RP cation channels in intestinal tissues, in which capsaicin seems to change the transport activity of H+/peptide co-transporter 1 (PEPT1), and to a lesser degree, it seems to alter the paracellular permeability of the intestinal epithelia.

DOI： 10.1248/bpb.30.547

Capsaicin-induced increase of intestinal cefazolin absorption in rats 査読

Yukiko Komori, Tetsuya Aiba, Chie Nakai, Risa Sugiyama, Hiromu Kawasaki, Yuji Kurosaki

Drug Metabolism and Pharmacokinetics 22 ( 6 ) 445 - 449 2007年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAP SOC STUDY XENOBIOTICS

The effect of capsaicin on intestinal cefazolin absorption was examined by means of an in situ closed loop method in rats to clarify whether the vanilloid receptor (TRPV1) is involved in drug absorption driven by passive diffusion. In control experiments with 1 mg/mL cefazolin, the amount of cefazolin absorbed from the closed loop was 15.3 +/- 1.5 mu g/cm in the rat jejunum. The absorption amount was increased to 22.8 +/- 0.9 and 23.4 +/- 2.4 mu g/cm when capsaicin was applied with cefazolin at concentrations of 10 and 400 mu M, respectively. The enhancing effect of capsaicin on cefazolin absorption was suppressed when ruthenium red, a non-selective inhibitor of transient receptor potential (TRP) cation channels, was intravenously infused into the rat during the experiment. Cefazolin accumulation in the intestinal tissue was not altered in the presence of capsaicin. Collectively, the mechanism accounting for the capsaicin-induced increase in the intestinal cefazolin absorption is probably that capsaicin associating with TRPV1 increases the intrinsic permeability of cefazolin in intestine.

DOI： 10.2133/dmpk.22.445

Evaluation of diffusion controlled vesicle (DCV) system for oral extended release by the in-vivo dissolution behaviop and the resulting pharmacokinetic profiles

Masanari Mabuchi, Kozo Tagawa, Tetsuya Aiba, Yuji Kurosaki

Drug Meatbolism Reviews 39 270 - 270 2007年

光に不安定な薬剤の簡易懸濁法を用いた投与方法について

座間味義人, 槙田崇志, 安藤哲信, 倉田なおみ, 合葉哲也, 黒崎勇二, 天野学, 名和秀起, 北村佳久, 千堂年昭, 五味田裕, 高山房子, 川崎博己

日本医療薬学会年会講演要旨集 16 323 - 323 2006年9月

バルプロ酸TDMデータの遡及的解析

槙田崇志, 上島智, 西原茂樹, 合葉哲也, 千堂年昭, 川崎博己, 五味田裕, 黒崎勇二

日本医療薬学会年会講演要旨集 16 553 - 553 2006年9月

Peritoneal dialysis alters tolbutamide pharmacokinetics in rats with experimental acute renal failure 査読

Tetsuya Aiba, Mizuki Horiuchi, Takashi Makita, Yukiko Komori, Hiromu Kawasaki, Yuji Kurosaki

Drug Metabolism and Pharmacokinetics 21 ( 4 ) 291 - 296 2006年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAP SOC STUDY XENOBIOTICS

The plasma concentration profile of the antidiabetic agent tolbutamide was investigated in glycerol-induced acute renal failure (ARF) rats receiving or not receiving peritoneal dialysis (PD) to assess the impact of performing dialysis on tolbutamide pharmacokinetics. It was revealed that the plasma concentration of tolbutamide was decreased by 23.4% by performing PD in ARF rats, while it was not changed by PD in normal rats. The decrease in the plasma concentration of tolbutamide was nearly proportional to the increase in its volume of distribution. To clarify the mechanisms responsible for the decreased tolbutamide concentration caused by PD, the plasma protein binding of tolbutamide was examined in normal and ARF rats. The plasma unbound fraction of tolbutamide was higher in ARF rats than in normal rats, and the dissociation constants were 3.5 +/- 0.7 and 5.5 +/- 0.2 mu g/mL in normal and ARF rats, respectively. These results indicated that the unbound fraction of tolbutamide was increased in ARF rats because of its protein binding being suppressed. It is therefore likely that since a measurable amount of tolbutamide can distribute in peritoneal dialysate in ARF rats, but not in normal rats, the plasma concentration of tolbutamide was decreased by performing PD only in ARF rats. These findings suggest that diabetes medication with tolbutamide should be carefully performed in patients receiving dialysis treatment.

DOI： 10.2133/dmpk.21.291

The effects of culture conditions on CYP3A4 and MDR1 mRNA induction by 1α,25- dihydroxyvitamin D3 in human intestinal cell lines, Caco-2 and LS180. 査読

Aiba T, Susa M, Fukumori S, Hashimoto Y

Drug Metabolism and Pharmacokinetics 20 ( 4 ) 268 - 274 2005年8月

Evaluation of phenytoin dosage regimens based on genotyping of CYP2C subfamily in routinely treated Japanese patients. 査読

Taguchi M, Hongou K, Yagi S, Miyawaki T, Takizawa M, Aiba T, Hashimoto Y

Drug Metabolism and Pharmacokinetics 20 ( 2 ) 107 - 116 2005年5月

Intestinal expression and metabolic activity of the CYP3A subfamily in female rats 査読

T Aiba, M Yoshinaga, K Ishida, Y Takehara, Y Hashimoto

Biological and Pharmaceutical Bulletin 28 ( 2 ) 311 - 315 2005年2月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The intestinal expression of the CYP3A subfamily was investigated in female rats, and the intestinal metabolism of two CYP3A substrates, testosterone and rifabutin, was examined and compared between males and females. CYP3A1/23 and CYP3A2 intestinal expression was barely detected in male and female rats. Although CYP3A9 was predominantly expressed in the female rat liver, its expression in the intestine was not different between the two sexes. The rate of testosterone 6beta-hydroxylation in the female intestine was similar to that for males. Rifabutin was also metabolized at similar rates in both intestines, although the metabolic rate was greater in the female liver. These results indicate that the intestinal drug metabolizing activity of the CYP3A subfamily is similar between males and females, and that CYP3A9 is involved in the intestinal metabolism of CYP3A substrates in both sexes.

DOI： 10.1248/bpb.28.311

Pharmacokinetic characterization of transcellular transport and drug interaction of digoxin in Caco-2 cell monolayers 査読

T Aiba, K Ishida, M Yoshinaga, M Okuno, Y Hashimoto

Biological and Pharmaceutical Bulletin 28 ( 1 ) 114 - 119 2005年1月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

To characterize the intestinal absorption of digoxin, its transcellular transport and drug interaction activity was investigated using Caco-2 cell monolayers. We examined digoxin transport in the presence and absence of ouabain to determine whether digoxin binding to Na+,K+-ATPase affects its transcellular digoxin transport, and evaluated its influx and efflux clearance by model-dependent pharmacokinetic analysis. Transcellular transport in the basal-to-apical direction was greater than that in the opposite direction. In addition, ouabain decreased the cellular accumulation of digoxin, but it did not alter its transcellular transport profile. The observations for transcellular transport and cellular accumulation in the presence of ouabain were used for the pharmacokinetic analysis, which showed that the efflux clearance of digoxin on the apical side of the monolayer was 15 times greater than that on the basal side. Apical-to-basal transport was increased by carvedilol and pimobendan, and these compounds suppressed the efflux clearance on the apical side and the influx clearance on the basal side. These findings indicate that the intestinal absorption of digoxin is primarily dominated by the efflux process on the luminal side of the intestine, and that carvedilol and pimobendan may vary the rate of intestinal digoxin absorption mainly by inhibiting its exsorptive transport.

DOI： 10.1248/bpb.28.114

小腸におけるCYP3A4発現調節活性の個体間変動因子の解明

合葉哲也

中冨健康科学振興財団第16回研究助成事業集 2005年

Caco-2細胞を用いた小腸の薬物吸収障壁機能の解析：ジゴキシン経細胞輸送と薬物相互作用メカニズムの速度論的評価

合葉哲也, 田口雅登, 橋本征也

臨床薬学の進歩 2005年

ビタミンD受容体によるCYP3A4発現誘導と生体防御のメカニズム

合葉哲也

ファルマシア 39 ( 5 ) 454 - 455 2003年5月

The increased intestinal absorption rate is responsible for the reduced hepatic first-pass extraction of propranolol in rats with cisplatin-induced renal dysfunction 査読

H Okabe, A Mizukami, M Taguchi, T Aiba, M Yasuhara, Y Hashimoto

JOURNAL OF PHARMACY AND PHARMACOLOGY 55 ( 4 ) 479 - 486 2003年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ROYAL PHARMACEUTICAL SOC GREAT BRITAIN

The mechanisms responsible for the increased bioavailability of propranolol in renal dysfunction were investigated in rats. Experimental acute renal failure (ARF) was induced by intraperitoneal injection of cisplatin (5 mg kg(-1)). ARF induced a significant increase in blood propranolol concentration after intra-intestinal administration. The extent of bioavailability (F) of propranolol at an intestinal dose of 15 mg kg(-1) was 16.4% and 26.9% in control and ARF rats, respectively, and the F value at a 37.5 mg kg(-1) dose was 54.7% and 81.4% in control and ARF rats, respectively. in contrast, the blood propranolol concentration following intraportal infusion was not increased significantly in ARF rats. The hepatic first-pass extraction (E-h) was dose-dependent and saturable: E-h of propranolol in control rats was 58.0% and 18.3% at 8 and 20 mg kg(-1), respectively, and E-h in ARF rats was 50.8% and 19.9% at 8 and 20 mg kg(-1), respectively. The initial absorption rate of propranolol from the intestine in ARF rats was significantly greater compared with control rats. These results indicated that the increased bioavailability of propranolol in rats with cisplatin-induced renal dysfunction was mainly a result of the increased absorption rate in the intestine followed by the partial saturation of hepatic first-pass metabolism.

DOI： 10.1211/002235702982

フェニトインの投与設計におけるCYP2C9と2C19遺伝子診断の有用性評価

内堀美和子, 田口雅登, 合葉哲也, 橋本征也, 本郷和久, 八木信一, 宮脇利男

臨床薬理 34 ( 1 ) 31S - 32S 2003年1月

Effect of experimental renal dysfunction on bioavailability of ajmaline in rats 査読

Hashimoto Y, Aiba T, Yasuhara M, Hori R

Journal of Pharmacy and Pharmacology 53 ( 6 ) 805 - 813 2001年6月

Single dose pharmacokinetics and pharmacodynamics of oxazepam in normal and renal dysfunction rats 査読

Kalpana Srivastava, Tomomi Hatanaka, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizumi

Biological and Pharmaceutical Bulletin 22 ( 6 ) 627 - 632 1999年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pharmaceutical Society of Japan

The purpose of this work was to investigate the disposition characteristics and pharmacodynamics of a benzodiazepine, oxazepam, in renal dysfunction rats. For the in vivo experiment, normal and renal dysfunction rats were given 40 mg/kg of oxazepam as the bolus dose. A quantitative electroencephalographic (EEG) method was used as the surrogate measure of the pharmacological response. The oxazepam concentration in plasma and cerebrospinal fluid (CSF) was assayed by the HPLC method. The steady-state volume of distribution and clearance based on total and unbound plasma did not change in renal dysfunction rats. Amplitude changes in the EEG induced by oxazepam in normal and renal dysfunction rats were characterized by a log- concentration response model or sigmoidal E(max) model. The pharmacodynamic parameters from these models were not altered in renal dysfunction. In in vitro binding studies for γ-aminobutyric acid (GABA)-benzodiazepine receptor complex, the oxazepam-induced effect was not potentiated by the plasma dialysate from renal dysfunction rats. Thus, it was suggested that the brain sensitivity to benzodiazepines was not altered in renal insufficiency.

DOI： 10.1248/bpb.22.627

Application of a non-linear dispersion model to analysis of the renal handling of p-aminohippurate in isolated perfused rat kidney 査読

Tetsuya Aiba, Shin Kubota, Tamotsu Koizumi

Biological and Pharmaceutical Bulletin 22 ( 6 ) 633 - 641 1999年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pharmaceutical Society of Japan

To analyze the renal handling of therapeutic compounds observed as a non-linear process with a diffusion phenomenon, we employed a non-linear dispersion model described with a partial differential equation and solved it by using the finite difference method with an implicit scheme in a model dependent analysis. In this study, the renal handling of p-aminohippurate (PAH) was investigated in isolated perfused rat kidney, in which a 50 μl bolus of injection solution containing [3]PAH and [14C]inulin was administered rapidly into the renal artery. The venous outflows were then collected for 15 min with a fraction collector. The renal extraction ratio of PAH was decreased from 65% to 18% as the PAH concentration in the injection solution was increased from 2 μM to 10 mM. The PAH outflow profile changed as the extraction process became saturated. With the non-linear dispersion model, the Miehaelis-Menten parameters for the PAH extraction process were estimated by a model fitting calculation. The calculated values were 0.83 μmol/min/kidney for V(max) and 89 μM for K(m). It was demonstrated that the model dependent analysis with a non-linear dispersion model is a useful approach to characterize renal drug handling, and is probably applicable for examining other non-linear processes which involve a diffusion phenomenon.

DOI： 10.1248/bpb.22.633

Effect of dosage form on stereoisomeric inversion of ibuprofen in volunteers 査読

Tetsuya Aiba, Mary M. Tse, Emil T. Lin, Tamotsu Koizumi

Biological and Pharmaceutical Bulletin 22 ( 6 ) 616 - 622 1999年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pharmaceutical Society of Japan

Twelve healthy volunteers were given ibuprofen racemate in two different dosage forms, a suspension and a tablet. The plasma concentration-time profiles of S- and R-ibuprofen were determined and the R-ibuprofen inversion clearance was calculated. Although the area under the curve was almost the same in both the suspension and tablet studies, the inversion clearance was larger in the suspension study than in the tablet study (1.18±0.65 and 0.72±0.63 l/h, shown as the mean±S.D.). The Michaelis-Menten parameters for this inversion process were then determined in vitro with human liver microsomes (1.3±0.2 mM for K(m) and 3.1±0.3 nmol/min/mg protein for V(max), shown as the mean±S.D.). These parameters indicated that the stereoisomeric inversion of R-ibuprofen in the liver was not likely to be saturated at the plasma concentrations measured in the volunteer study. The profile of the plasma concentration ratio between S-ibuprofen and R-ibuprofen revealed a difference in the early phase of these two studies. Therefore the inversion difference between those two studies probably resulted from the difference in the absorption phase of each dosage form. Our study demonstrated that R- ibuprofen inversion could be affected by alteration of dosage form.

DOI： 10.1248/bpb.22.616

Influence of pH on skin permeation of amino acids

Tomomi Hatanaka, Toshihiko Kamon, Chisato Uozumi, Setsuko Morigaki, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizumi

Journal of Pharmacy and Pharmacology 48 ( 7 ) 675 - 679 1996年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Blackwell Publishing Ltd

Skin permeation of amino acids through excised rat skin was measured at various pH values. The permeabilities varied with the donor pH and amino acid, indicating that each ionic species of amino acid may have a different permeability. The permeability coefficient of each ion was estimated from the permeability-pH profiles using the dissociation constants. The estimated values for mono-cation and uncharged zwitterion were not dependent on the lipophilicity but on the size of the amino acid, suggesting a porous mechanism of transport. The permeability coefficient was highest for di-cation, followed by mono-cation, positively charged, uncharged and negatively charged zwitterions. The electrical potential difference across the skin was too small to affect the permeation of ions. The permselective property of skin thus seems to be determined by the difference of diffusivity in aqueous pores of skin due to the hydration of ions and other factors.

DOI： 10.1111/j.2042-7158.1996.tb03949.x

A study of the hydrophilic cellulose matrix: Effect of drugs on swelling properties

Suwannee P. Panomsuk, Tomomi Hatanaka, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizumi

Chemical and Pharmaceutical Bulletin 44 ( 5 ) 1039 - 1042 1996年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Pharmaceutical Society of Japan

The swelling properties of hydrophilic cellulose matrices were studied using three drugs having different water solubility: indomethacin, theophylline, and mannitol. Two swelling parameters: maximum swelling index (V) and the apparent diffusion coefficient of water in the matrix (D(w)), were calculated from the swelling data and were used to describe structures and properties of the swollen matrices. The V value indicates the swelling extent as well as the capacity of maintaining the matrix shape, whereas D(w) represents the swelling rate that also reflects the structural resistance of the polymer network against the movement of water molecules. The results show that both polymers and incorporated drugs influence the swelling properties of the matrices. Polymers that contain more hydroxypropoxyl group produce matrices with high integrity, even in the presence of drugs. V values indicated that the capacity of the matrices to maintain their shape depends on polymer (i.e., the swelling part). The effect of drug solubility can be seen from D(w) values. For a highly water-soluble drug, the structural resistance of the swollen matrices is mainly governed by the drug. In contrast, this is primarily influenced by the polymer in the case of drugs that are slightly or poorly water soluble.

DOI： 10.1248/cpb.44.1039

A study of the hydrophilic cellulose matrix: Effect of indomethacin and a water-soluble additive on swelling properties

Suwannee P. Panomsuk, Tomomi Hatanaka, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizumi

International Journal of Pharmaceutics 126 ( 1-2 ) 147 - 153 1995年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

A swelling measurement device was designed to observe the axial swelling direction of a matrix containing various types of hydrophilic cellulose derivatives (methylcellulose, hydroxypropylmethylcellulose and hydroxypropylcellulose). The effect of indomethacin and lactose on the swelling properties was also studied. The maximum swelling index and the apparent diffusion coefficient of water in the matrix, calculated from the swelling data, were used to describe the swelling properties of the matrix, reflecting the matrix integrity. The results showed that hydroxypropylcellulose produced a matrix with a high integrity. Indomethacin and lactose changed the swelling properties of the hydrophilic cellulose matrices in this study. © 1995.

DOI： 10.1016/0378-5173(95)04113-3

Effect of pH on the skin permeability of a zwitterionic drug, cephalexin

Tomomi Hatanaka, Setsuko Morigaki, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizumi

International Journal of Pharmaceutics 125 ( 2 ) 195 - 203 1995年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Skin permeability of the zwitterionic drug, cephalexin, was measured at various pH. A U-shaped curve was obtained for the relationship between the permeability coefficient and pH. Although cephalexin degraded dependent on the pH, the concentration in the suspended donor solution was maintained constant by the high dissolution rate. The barrier function of skin, which was assessed by the permeation of the nonelectrolytes, cortisone and o-mannitol, did not change over the range from pH 3.0 to 7.0. The permeability coefficient of cephalexin decreased with increase in zwitterion fraction and decrease in fractions of cation and anion, suggesting that each ionic species has different skin permeability. The permeability coefficient of zwitterion, estimated on this assumption of each ionic species having different permeability, was about 10% that of cation and anion. The octanol/buffer distribution coefficient and diffusion coefficient were also lower for zwitterion than for cation and anion. This suggests that the pH dependency in skin permeability of cephalexin may reflect the permselective property of skin dependent on the lipophilicity and/or diffusivity of ionic species. © 1995.

DOI： 10.1016/0378-5173(95)00113-W

Effects of probenecid and cimetidine on the renal excretion of 3’-azido-3’-deoxy-thymidine in rats 査読

Aiba T, Sakurai Y, Tsukada S, Koizumi T

Journal of Pharmacology and Experimental Therapeutics, 272(1): 94-99 272 ( 1 ) 94 - 99 1995年1月

A Study of the Hydrophilic Cellulose Matrix: Effect of Indomethacin and a Water-Soluble Additive on Release Mechanisms

Suwannee P. Panomsuk, Tomomi Hatanaka, Tetsuya Aiba, Kazunori Katayama, Tamotsu Koizum

Chemical and Pharmaceutical Bulletin 43 ( 6 ) 994 - 999 1995年

記述言語：英語掲載種別：研究論文（学術雑誌）

The release profile of indomethacin (IM) from a direct compressible matrix containing three hydrophilic cellulose derivatives, methylcellulose (MC25 and MC50), hydroxypropylcellulose (HPC140), and hydroxypropylmethylcellu-lose (HPMC50) was studied. The drug release profile was affected by matrix size, polymer type, drug: polymer ratio and water soluble additive (lactose). An IM zero-order release matrix can be obtained by mixture and direct compression with MC50, HPMC50 and HPC140. The release rate from the MC50 and HPC140 matrix can be modified by replacing MC50 or HPC140 with MC25, and a zero-order release could be obtained even when the amount of replacement with MC25 is up to 35 and 45%, respectively. Lactose up to 10% slightly affected the release profile. IM released from this kind of matrix by a zero-order rate seems to be controlled by the swelling and relaxation of the polymer. © 1995, The Pharmaceutical Society of Japan. All rights reserved.

DOI： 10.1248/cpb.43.994

Kinetic Analysis of Neuromuscular Blockade. I. Relationship between Twitch Depression and Stimulation Frequency after d-Tubocurarine Administration. 査読

田島武志, 金子和代, 畑中朋美, 合葉哲也, 片山和憲, 小泉保

Biological and Pharmaceutical Bulletin 17 ( 8 ) 1083 - 1088 1994年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：公益社団法人日本薬学会

The degree of twitch depression induced by nondepolarizing neuromuscular blocking drugs is known to be dependent on the stimulation frequency employed. Train-of-four (TOF) stimulations with different frequencies (0.67, 1.33 and 2.0Hz) were delivered to a sciatic nerve of a rat and series of four twitch heights of a tibialis anterior muscle were measured after d-tubocurarine (d-TC) administration. With a decrease of stimulus interval, twitch heights were intensely depressed. We hypothesized that the oservations are due to the changes of released amount of neuromuscular transmitter, acetylcholine, dependent on stimulus interval, and a pharmacokinetic/pharmacodynamic model based on the hypothesis was proposed. The model allowed simultaneous fitting of the twitch height depression after d-TC administration. It also could give a rationale to the fact that TOF stimulation at 2.0 Hz is a more sensitive monitoring method of neuromuscular function than single twitch stimulation (0.1-0.2 Hz).

DOI： 10.1248/bpb.17.1083

その他リンク： http://search.jamas.or.jp/link/ui/1995191748

Kinetic Analysis of Neuromuscular Blockade. II. Train-of-Four Fade Induced by d-Tubocurarine and .ALPHA.-Bungarotoxin. 査読

田島武志, 加藤安宏, 畑中朋美, 合葉哲也, 片山和憲, 小泉保

Biological and Pharmaceutical Bulletin 17 ( 8 ) 1089 - 1093 1994年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：公益社団法人日本薬学会

The degree of train-of-four (TOF) fade, i.e., the reduction of the fourth to the first twitch height in a train, induced by d-tubocurarine (d-TC) and α-bungarotoxin (α-BX) was investigated. The fade induced by d-TC was pronounced in comparison with that by α-BX, and the difference was analyzed using a kinetic model. Based on the assumptions : (1) Acetylcholine (ACh) binds to the nicotinic receptor and evokes twitch response. (2) The amount of released ACh is dependent on stimulus interval. (3) d-TC interacts competitively with the receptor. (4) α-BX interacts irreversibly with the receptor. It was suggested that the fade by d-TC and α-BX can be explained by the difference of the receptor occupancy by ACh which was caused by different interaction mechanisms of the two muscle relaxants with receptors.

DOI： 10.1248/bpb.17.1089

その他リンク： http://search.jamas.or.jp/link/ui/1995191747

Renal handling of tobramycin in the isolated perfused rat kidney 査読

Tetsuya Aiba, Yoshie Itoga, Hiromasa Shimizu, Yusuke Tanigawara, Ryohei Hori

Journal of Pharmaceutical Sciences 83 ( 5 ) 723 - 726 1994年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

The renal handling of tobramycin (TOB), an aminoglycoside antibiotic (AG), was studied using a single‐pass isolated perfused rat kidney with moment analysis. In the bolus administration study at tracer concentration (7.4 μM), 32% of the glomerular‐filtrated TOB remained in the lumen, but no TOB was found in the vein. This ratio of the luminal uptake was reduced in a dose‐dependent manner. Other aminoglycosides such as gentamicin inhibited this uptake, but tetraethylammonium and glucosamine had no effect. In addition, under the alkalinuria condition, TOB uptake was decreased to 67% of the control value. This indicated that TOB has mainly been taken into the renal epithelial cells from their luminal site and that this uptake process was saturable and specific for AGs which have more than one cationic group. The present findings should be helpful in developing a method to reduce the nephrotoxicity of AGs and to identify their toxicity mechanisms. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/jps.2600830526

Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney 査読

HORI R

J. Pharmacol. Exp. Ther. 266 ( 3 ) 1620 - 16258520/ 1993年3月

Effect of l-menthol on the permeation of indomethacin, mannitol and cortisone through excised hairless mouse skin 査読

片山和憲, 高橋修, 松井良幹, 森垣説子, 合葉哲也, 掛見正郎, 小泉保

Chem Pharm Bull 40 ( 11 ) 3097 - 3099 1992年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：公益社団法人日本薬学会

The effect of l-menthol on the skin permeability of mannitol, cortisone or indomethacin was examined by an in vitro penetration technique with hairless mouse skin. The donor solution was prepared with phosphate buffered saline, ethanol : buffered saline (20 : 80,v/v) or ethanol : buffered saline (20 : 80,v/v) containing 1% (w/v) l-menthol. Although ethanol showed little enhancing effect, l-menthol in an aqueous ethanol vehicle at pH 7.4 increased the permeability coefficients of mannitol and indomethacin by about 100 times that of the control (an aqueous vehicle) and increased that of cortisone by about 10 times. l-Menthol, however, scarcely enhanced the penetration of indomethacin at pH 3.0,the majority of the species being in unionized form. These results suggested that the menthol-ethanol-aqueous system enhanced skin permeability through a direct effect on the polar and/or lipid pathways, while the thermodynamic activity of the penetrant molecule in the delivery vehicle might also influence the effectiveness of the penetration enhancer.

Moment analysis of drug disposition in kidney. II: Urine pH‐dependent tubular secretion of tetraethylammonium in the isolated perfused rat kidney 査読

Akira Kamiya, Yusuke Tanigawara, Yoshihiro Saito, Yoshie Hayashi, Tetsuya Aiba, Ken‐Ichi Inui, Ryohei Hori

Journal of Pharmaceutical Sciences 79 ( 8 ) 692 - 697 1990年

記述言語：英語掲載種別：研究論文（学術雑誌）

Effects of urine pH on the renal tubular secretion of an organic cation (tetraethylammonium, TEA) and an organic anion (p‐aminohippurate, PAH) were investigated using the isolated erythrocyte‐perfused rat kidney. The method was based on a multiple indicator dilution experiment and noncompartmental moment analysis. Treatment with sodium bicarbonate and sodium dihydrogen phosphate increased and decreased urine pH, respectively, but affected neither the condition of the perfused kidney nor the renal handling of albumin and inulin. In TEA studies, the increase of urine pH prolonged the mean residence time in renal epithelial cells (T̄cell) and reduced the apparent secretion intrinsic clearance, but did not influence the volume of distribution in the kidney (Vddrug). The decrease of urine pH did not affect these kinetic parameters. By contrast, PAH secretion was constant against the change of urine pH. Since any change in the basolateral membrane transport is reflected in Vddrug, the net transport from blood to cells can be regarded as similar under these treatments. On the other hand, the prolonged T̄cell of TEA with the increased urine pH suggested a slow transport from cells to lumen across the brush‐border membranes. The present results coincide with the hypothetical mechanism that organic cations are secreted via an active transport system, coupled to the countertransport of H+ into cells. In conclusion, the present method is useful to separately evaluate the transmembrane transport across both sides of the renal epithelial cells in a morphologically intact kidney. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/jps.2600790809

Moment analysis of drug disposition in kidney. III: Transport of p‐aminohippurate and tetraethylammonium in the perfused kidney isolated from uranyl nitrate‐induced acute renal failure rats 査読

Yusuke Tanigawara, Yoshihiro Saito, Tetsuya Aiba, Kou Ohoka, Akira Kamiya, Ryohei Hori

Journal of Pharmaceutical Sciences 79 ( 3 ) 249 - 256 1990年

記述言語：英語掲載種別：研究論文（学術雑誌）

A different manner of insufficiency of renal epithelial cell transport between the organic anion and cation, p‐aminohippurate and tetraethylammonium, respectively, was observed in the perfused kidney isolated from uranyl nitrate‐induced acute renal failure (ARF) rats. The single‐pass outflow pattern of the perfused kidney was analyzed by noncompartmental moment analysis. The active tubular secretion was impaired faster than the reduction of glomerular filtration, and the tetraethylammonium secretion decreased at an earlier stage of ARF than p‐aminohippurate. The apparent uptake rate constant from blood to cells of p‐aminohippurate was reduced with the progress of ARF and associated with the amount of this drug secreted, whereas the uptake rate constant of tetraethylammonium did not change until the late stage of ARF. The mean residence time in renal epithelial cells of tetraethylammonium was prolonged with reduction of the amount to be secreted, while that of p‐aminohippurate remained unchanged. Therefore, the uptake of p‐aminohippurate across the basolateral membranes decreased gradually, and the transport across the brush border membranes was still unchanged after uranyl nitrate treatment. On the other hand, the secretion of tetraethylammonium from cells to lumen was impaired at first, and then the uptake from blood to cells was impaired. These results suggest that impairment by uranyl nitrate‐induced ARF appears at the carrier‐mediated transport process of the epithelial cell membranes for both organic anions and cations. Copyright © 1990 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/jps.2600790315

Moment analysis of drug disposition in kidney: Transcellular transport kinetics of p‐Aminohippurate in the Isolated Perfused Rat Kidney 査読

Ryohei Hori, Yusuke Tanigawara, Yoshihiro Saito, Yoshie Hayashi, Tetsuya Aiba, Katsuhiko Okumura, Akira Kamiya

Journal of Pharmaceutical Sciences 77 ( 6 ) 471 - 476 1988年

記述言語：英語掲載種別：研究論文（学術雑誌）

The mean renal epithelial cell residence time, T̄cell, was defined as a model‐independent characteristic of the transcellular transport process in the isolated perfused kidney. The transcellular transport process includes transport at the basolateral membrane, diffusion in the cytosol, and transport at the brush border membrane. The parameter T̄cell represents the mean time for the drug secreted from the tubules to pass through the renal epithelial cells, and is calculated as the difference of the mean urinary transit time between secreted drug and inulin in the single‐pass perfusion system. Therefore, the urinary excretion rate–time course is indispensable to evaluate T̄cell. p‐Amino‐hippuric acid was used as a model compound. The bovine erythrocytes in the perfusate kept the isolated kidney in an almost constant physiological condition, including secretion function. The renal vein outflow curves were also analyzed by the use of moments. The dispersion in the catheter was corrected by a deconvolution. The apparent secretion intrinsic clearance and the apparent volume of distribution were calculated from the moments. The present method will be useful for analysis of the transcellular transport mechanism and the effect of disease states on renal transport of drugs. Copyright © 1988 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/jps.2600770602

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