Faculty Profiles - AIBA Tetsuya

Capsaicin-induced increase of intestinal cefazolin absorption in rats Reviewed

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

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

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

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 2006.9

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 2006.9

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

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

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed

Aiba T, Susa M, Fukumori S, Hashimoto Y

Drug Metabolism and Pharmacokinetics 20 ( 4 ) 268 - 274 2005.8

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

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

Drug Metabolism and Pharmacokinetics 20 ( 2 ) 107 - 116 2005.5

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

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

Biological and Pharmaceutical Bulletin 28 ( 2 ) 311 - 315 2005.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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

Biological and Pharmaceutical Bulletin 28 ( 1 ) 114 - 119 2005.1

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

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

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 2003.5

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

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

JOURNAL OF PHARMACY AND PHARMACOLOGY 55 ( 4 ) 479 - 486 2003.4

Language：English Publishing type：Research paper (scientific journal) Publisher：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 2003.1

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

Hashimoto Y, Aiba T, Yasuhara M, Hori R

Journal of Pharmacy and Pharmacology 53 ( 6 ) 805 - 813 2001.6

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

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

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

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

Tetsuya Aiba, Shin Kubota, Tamotsu Koizumi

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

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

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

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

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

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