Details of a Researcher - Ohtani, Hisakazu

Papers - Ohtani, Hisakazu

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Decrease in ciprofloxacin absorption by polyvalent metal cations is not fully attributable to chelation or adsorption.

Imaoka A, Hattori M, Akiyoshi T, Ohtani H*.

Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics) 29 ( 5 ) 414 - 418 2014.05

Research paper (scientific journal), Joint Work, Accepted, ISSN 1347-4367

The drug interaction between new quinolone antibiotics (NQs) and polyvalent metal cation products, leading to a significant decrease in the absorption of NQ, is considered to be attributable to the formation of poorly absorbable chelate and physicochemical adsorption of NQs to cation products. To clarify the mechanisms of this drug interaction in detail, we investigated the effects of Al3+ or Mg2+ on the membrane permeation profile of ciprofloxacin (CPFX) across human colon carcinoma cell lines (Caco-2) in monolayer culture, and characterized the adsorption nature of CPFX to polyvalent metal cation products under physiological conditions. As a result, Al3+ or Mg2+ partially but not fully impaired the permeation of CPFX across Caco-2 monolayer up to 30% or 60% of control, respectively. Physicochemical adsorption of CPFX to cation products was not observed under physiological pH. In conclusion, two possible mechanisms investigated, the decrease in the permeability of CPFX by chelate formation and adsorption of CPFX to polyvalent metal cation products, may partially but not fully explain the extent of the drug interaction clinically observed.

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OTC薬実習の問題点とその改善のための提案.

剱田侑希, 門田佳子, 鈴木小夜, 青森達, 小林典子, 高木彰紀, 手塚淑人, 大谷壽一, 中村智徳*.

医療薬学 ((一社)日本医療薬学会) 40 ( 2 ) 117-123 - 123 2014.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 1346-342X

平成24年度薬局実務実習を終了した大学薬学部5年生を対象にアンケート調査を行い一般用医薬品(over-the-counter drug、OTC薬)実習改善のための方策について検討した。全体集計には回収分(158名、回収率94.6%)を使用し、記入漏れのない回答を有効回答とし、統計解析により有効回答(152名、有効回答率91.0%)のみを使用した。薬局OTC薬実習において27.8%(44名)の学生が来局者に対し、販売することができ、18.4%(29名)の学生が相談販売を行うことができた。相談販売を行った学生の中には指名販売を含めると50回以上販売できた学生が2名いた。一方で、販売、ロールプレイ(RP)、OTC薬販売の見学など、演習形式の実習のいずれも実施しない学生が11.4%(18名)いた。OTC薬実習に対する学生の「興味」「十分な実施」「満足度」に関しては実施状況による差がみられた。

Characterization of transplacental transfer of paroxetine in perfused human placenta: development of a pharmacokinetic model to evaluate tapered dosing.

Nagai M, Ohtani H, Satoh H, Matsuoka S, Hori S, Fujii T, Taketani Y, Sawada Y*.

Drug Metabol Dispos (Drug Metabolism and Disposition) 41 ( 12 ) 2124 - 2132 2013.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

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Effect of aromatase inhibitors on bone mineral density in Japanese breast cancer population.

Akiyoshi T, Shimomura Y, Masuda S, Okamoto Y, Hiura S, Kato H, Asayama T, Ohtani H*.

Drug Metabol Pharmacokinet (Drug Metabolism and Pharmacokinetics) 25 ( 5 ) 446 - 450 2013.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

We retrospectively analyzed the bone mineral density (BMD) of postmenopausal Japanese women taking an aromatase inhibitor (AI), exemestane, anastrozole or letrozole, and calculated the decrease rate constant of BMD in each individual to compare the influence of the three AIs on BMD. We also aimed to evaluate the preventive effect of bisphosphonates (BPs) on the AI-induced decrease in BMD. The decrease rate constant of BMD (ke) in each individual was determined as a slope of linear regression of the relationship between time and logarithm of BMD value in each patient during the AI therapy. To compensate for the age-related change in BMD level, we estimated the age-related decrease rate constant of BMD (ke,0) in healthy Japanese postmenopausal women from the literature. AIs decreased BMD with a ke value of -0.0329 yr-1, which was 4.7-fold larger than the ke,0 value of -0.00699 yr-1. No significant difference was detected in the influence on BMD among AIs. Co-administration of BP ameliorated the ke value to -0.0117 yr-1, a value similar to ke,0. The influence of AIs on BMD was quantitatively evaluated by using the decrease rate constant of BMD (ke). The present study also suggests that BPs may be useful to prevent the decrease in BMD induced by AIs. © 2013 by the Japanese Society for the Study of Xenobiotics (JSSX).

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Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants.

Akiyoshi T, Ito M, Murase S, Miyazaki M, Guengerich F, Nakamura K, Yamamoto K, Ohtani H*.

Drug Metabol Pharmacokinet (Drug Metabolism and Pharmacokinetics) 25(5) ( 5 ) 411 - 415 2013.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 13474367

Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a timedependent manner. The maximum inactivation rate constants, kinact,max, of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The KI values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI. © 2013 by the Japanese Society for the Study of Xenobiotics (JSSX).

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Pharmacokinetic model incorporating mechanism-based inactivation of CYP2D6 can explain both non-linear kinetics and drug interactions of paroxetine.

Mikami A, Ohtani H, Hori S, Sawada Y*.

Int J Clin Pharmacol Ther (International Journal of Clinical Pharmacology and Therapeutics) 51(5) ( 5 ) 374-382 - 382 2013.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 09461965

Objective: To develop a pharmacokinetic model able to describe the nonlinear pharmacokinetics of paroxetine (PRX) and to predict the drug-drug interaction between PRX and metoprolol under various dosage regimens. Methods: A pharmacokinetic model of PRX incorporating mechanism-based inhibition was developed. This model was fitted to the drug concentration profiles obtained after single and repeated administrations of PRX to estimate the pharmacokinetic parameters of PRX and degradation rate constant of cytochrome P450 (CYP) 2D6. It was also fitted to the time profile of S-metoprolol after coadministration of metoprolol and PRX, and the fractional contribution of CYP2D6 to overall clearance of S-metoprolol was estimated. Using the developed model and estimated parameters, an optimal dosage regimen for metoprolol during withdrawal of PRX was simulated. Results: The developed model well described the time profiles of both PRX and metoprolol concentration during concomitant administration. The estimated parameters were consistent with reported values. The nonlinear and accumulation properties of PRX could be explained by mechanism-based inhibition of CYP2D6 by PRX. Upon tapering PRX from 20 mg/day to 10 mg/day for 14 days then 5 mg/day for 14 days until cessation, the optimal dosage regimen to resume 120 mg/day of metoprolol based on the developed model was as follows: 30 mg/day during concomitant administration, 40 mg/day for the next 14 days, 60 mg/day for the next 14 days, and finally 120 mg/day. Conclusions: The developed model enabled us to quantitatively estimate drug-drug interactions of PRX and CYP2D6 substrate drugs, and to predict optimal dosage regimens. © 2013 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965.

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Stability of the admixture of trace elements and vitamin-containing TPN solution in a multi-chamber bag (Fulcaliq).

Okuyama Y, Akiyoshi T, Asayama T, Hirai M, Matsuyama K Ohtani H* .

The Journal of Asian Association of Schools of Pharmacy 1(3) 152-158 2012.09

Research paper (scientific journal), Joint Work, Accepted

Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies.

Shintaku K, Hori S, Satoh H, Tsukimori K, Nakano H, Fujii T, Taketani Y, Ohtani H, Sawada Y*.

Br J Clin Pharmacol (British Journal of Clinical Pharmacology) 73(2) ( 2 ) 248-256 - 256 2012.02

Research paper (scientific journal), Joint Work, Accepted, ISSN 03065251

Aim: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in full-term pregnant women leads to fetal or neonatal toxicity, such as constriction of the ductus arteriosus (DA) and persistent pulmonary hypertension in the newborn. The aim of this study was to predict quantitatively the fetal toxicity of three NSAIDs (antipyrine, salicylic acid and diclofenac) using the transplacental pharmacokinetic parameters obtained from our previous placental perfusion studies. Methods Human fetal plasma concentration profile after oral administration of each NSAID to the mother was estimated using the transplacental pharmacokinetic parameters and pharmacokinetic parameters in adult women. The fetal plasma concentration-response relationship for the three NSAIDs was estimated by pharmacokinetic/pharmacodynamic analysis of the results of previous studies investigating the effects of NSAIDs on the ratio of inner diameter of the DA to that of the pulmonary artery (DA/PA) in rats and the plasma concentration profiles of NSAIDs in pregnant rats. Results The risk of constriction of the DA was well predicted by the model. Mean DA/PA ratio after oral administration of diclofenac to the mother was estimated to be 39.0%, whereas both of the corresponding values after oral administration of antipyrine and salicylic acid were estimated to be 5.9%. These results suggest that the fetal risk of diclofenac is higher than those of salicylic acid and antipyrine. Conclusions This study presents a novel approach to predict quantitatively the fetal risk of NSAIDs administered to the mother. Human placental perfusion study and pharmacokinetic/pharmacodynamic analysis may provide basic data for predicting human fetal toxicity of drugs. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

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Warfarin and miconazole oral gel interactions: Analysis and therapy recommendations based on clinical data and a pharmacokinetic model

Miki A., Ohtani H., Sawada Y.

Journal of Clinical Pharmacy and Therapeutics (Journal of Clinical Pharmacy and Therapeutics) 36 ( 6 ) 642 - 650 2011.12

ISSN 02694727

Summary What is known and Objective: Miconazole is a strong inhibitor of CYP2C9, one of the main enzymes involved in the metabolism of warfarin. Concurrent use of the two drugs leads to potentially serious adverse effects. Although it is often assumed that use of the oral miconazole gel is acceptable with concomitant warfarin, because of the low bioavailability following buccal administration, drug-drug interactions have been reported following such use. We aimed to investigate case reports of such interactions and develop a pharmacokinetic model to model such interactions. Methods: The Medline database from 1966 to October 2010 was used for literature search. Case reports of the potentiation of the anticoagulant effects of warfarin, such as the elevation of prothrombin time (INR), by concomitant administration of warfarin and miconazole oral gel were collected. We quantitatively estimated the extent of inhibition of warfarin metabolism by orally administered miconazole gel and compared our findings with case reports. Results and Discussion: Metabolism of (S)-warfarin is inhibited potently following administration of a standard dose (200-400 mg/day in Japan) of miconazole gel. This may lead to in an increase in the blood concentration of warfarin and lead to serious adverse effects. The literature reports of clinical interactions with concomitant use of those drugs show that other factors may amplify the effects of any increase in blood concentration. What is new and Conclusion: We summarize all reported, clinically significant, cases of drug interaction between miconazole oral gel and warfarin. Pharmacokinetic modelling shows that concomitant administration of warfarin and miconazole oral gel can lead to substantial increase in warfarin concentration. However, our PK/PD model fails to capture the dramatic increases seen in INR values, and hence bleeding complications, reported in the literature. Taken together, the evidence suggests that concomitant use of miconazole gel and warfarin should be avoided. Even over-the-counter products containing miconazole should be used with caution by patients receiving warfarin. © 2010 Blackwell Publishing Ltd.

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Model analysis of tulobuterol patch formulations to explain the influence of drug release rate and transdermal transfer rate on the plasma concentration profile

Watanabe T., Satoh H., Hori S., Miki A., Ohtani H., Sawada Y.

Yakugaku Zasshi (Yakugaku Zasshi) 131 ( 10 ) 1483 - 1492 2011.10

ISSN 00316903

The purpose of this study was to compare the transdermal transfer profiles of brand and generic tulobuterol patch formulations and to evaluate possible changes of in vivo kinetics resulting from increased transdermal transfer by means of pharmacokinetic analysis using reported in vitro drug release rate data and plasma drug concentration profiles. On the assumption that the transdermal transfer rate constant (k2) would be constant (independent of formulation), the drug release rate constant from patch formulation (k1) was predicted to be almost equal to the k2 value (k1≈k2) in the brand formulation, but 2- to 4-fold higher than the k2 value (k1>k2) in the two generic formulations. Under normal conditions, there would be no marked difierence in the plasma concentration profiles among the formulations. However, under conditions where transdermal transfer is increased (that is, higher k2), the plasma tulobuterol concentration was predicted to increase more rapidly, with higher C max, and then to decrease more rapidly in the elimination phase after applying the generic formulations compared with the brand formulation. These difierent behaviors would be seen because the transdermal transfer of the generic formulations would be afiected by k2, whereas k1 is still rate-determining for the brand formulation. These results suggest that bronchial asthma patients with risk factors for impaired skin barrier function, including atopic dermatitis, long-term treatment with steroids, and advanced age, should be carefully monitored for reduced treatment efficacy or adverse drug reactions after application of rapid-release generic tulobuterol patch formulations. © 2011 The Pharmaceutical Society of Japan.

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Bottom-up modeling and simulation of tacrolimus clearance: Prospective investigation of blood cell distribution, sex and CYP3A5 expression as covariates and assessment of study power.

Ohtani H*, Barter Z, Minematsu T, Makuuchi M, Sawada Y, Rostami-Hodjegan A.

Biopharm Drug Dispos (Biopharmaceutics and Drug Disposition) 32(9) ( 9 ) 498-506 - 506 2011.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 01422782

The objectives were to investigate the ability of population-based in vitro-in vivo extrapolation (IVIVE) to reproduce the influence of haematocrit on the clearance of tacrolimus, observed previously, and to assess the power of clinical studies to detect the effects of covariates on the clearance of tacrolimus. A population-based pharmacokinetic simulator (Simcyp) was used to simulate tacrolimus clearance from in vitro metabolism data and demographic characteristics of Japanese liver transplant patients (JLTs). The relationship between haematocrit and dose-to-concentration (D/C) ratio was validated using seven JLTs, whose highly variable haematocrit and D/C ratio were previously analysed. This validation was used as a surrogate for establishing 'interindividual' variability and to assess the power of clinical studies to discern the effect of haematocrit, sex and CYP3A5 genotype on tacrolimus clearance in a virtual JLT population. The relationship between haematocrit and D/C ratio was reproducible by Simcyp and corresponded well to those observed in seven JLTs. The number of JLTs required to detect the influence of CYP3A5 genotype and sex were estimated to be about 50 and > 600, respectively, which was consistent with the results of previous population pharmacokinetic studies for tacrolimus. In conclusion, population-based IVIVE is considered to be a useful approach to assess the influence of covariates a priori before conducting clinical studies. This is also helpful with study design and assessment of the statistical power of clinical studies involving population-based pharmacokinetics to detect the effects of covariates. Copyright © 2011 John Wiley & Sons, Ltd.

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Model analysis of tulobuterol patch formulation to explain the influence of drug release rate and transdermal transfer rate on the plasma concentration profile.

Watanabe T, Satoh H, Hori S, Miki A, Ohtani H, Sawada Y*.

Yakugaku Zasshi 131(10) 1483-1492 2011.10

Research paper (scientific journal), Joint Work, Accepted

ツロブテロール貼付後の血漿中濃度に及ぼす製剤特性と皮膚透過性の影響に関する薬物動態学的解析

渡邉哲夫, 佐藤宏樹, 堀里子, 三木晶子, 大谷壽一, 澤田康文

薬学雑誌 ((公社)日本薬学会) 131 ( 10 ) 1483 - 1492 2011.10

ISSN 0031-6903

気管支喘息治療に適応をもつツロブテロールの全身作用型経皮吸収製剤であるホクナリンテープは、持続的な薬物放出制御システム(結晶レジンボアシステム)により、過度な血中濃度上昇を抑制することで全身性の副作用(振戦や心悸亢進など)を軽減し、さらに長時間作用を持続させることでモーニングディップ(早朝の喘息発作)を抑制することが示されている。ツロブテロール貼付剤にはホクナリンテープ以外にも複数の後発医薬品が承認されており、生物学的同等性試験により先発医薬品と同等であることが検証されている。しかし、後発医薬品では結晶レジンボアシステムは採用されておらず、ツロブテロールの放出がホクナリンに比べて速いことがin vitroの実験で示されている。臨床的にも、先発医薬品で喘息症状が良好にコントロールされていた患者が後発医薬品への切替え後に症状増悪した症例や副作用(振戦)が出現した症例が報告されている。そこで今回、先発医薬品から後発医薬品への切替えにより生じうる影響について検討するため薬物動態学的解析を行った。その結果、後発医薬品の血中移行性は皮膚透過性の影響を受けやすく、皮膚透過性が高まっている患者ではツロブテロールの副作用リスク増大や治療効果減弱をきたしうることが示唆された。

災害時における薬物治療の注意点-「薬が飲めない使えない」「生活・体調の変化」に対応した薬学的管理-.

澤田康文, 三木晶子, 堀里子, 佐藤宏樹, 大谷壽一, 大津史子.

日本病院薬剤師会雑誌 (日本病院薬剤師会) 47(9) 1101-1113 2011.09

Joint Work

Comparison of the inhibitory profiles of itraconazole and cimetidine in cytochrome P450 3A4 genetic variants.

Akiyoshi T, Saito T, Murase S, Mitsue Miyazaki M, Murayama N, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Ohtani H*.

Drug Metab Dispos (Drug Metabolism and Disposition) 39(4) ( 4 ) 724-8 - 728 2011.04

Research paper (scientific journal), Joint Work, Accepted, ISSN 00909556

CYP3A4, an important drug-metabolizing enzyme, is known to have genetic variants. We have previously reported that CYP3A4 variants such as CYP3A4.2, 7, 16, and 18 show different enzymatic kinetics from CYP3A4.1 (wild type). In this study, we quantitatively investigated the inhibition kinetics of two typical inhibitors, itraconazole (ITCZ) and cimetidine (CMD), on CYP3A4 variants and evaluated whether the genetic variation leads to interindividual differences in the extent of CYP3A4-mediated drug interactions. The inhibitory profiles of ITCZ and CMD on the metabolism of testosterone (TST) were analyzed by using recombinant CYP3A4 variants. The genetic variation of CYP3A4 significantly affected the inhibition profiles of the two inhibitors. In CYP3A4.7, the Ki value for ITCZ was 2.4-fold higher than that for the wild-type enzyme, whereas the Ki value for CMD was 0.64-fold lower. In CYP3A4.16, the Ki value for ITCZ was 0.54-fold lower than that for wild-type CYP3A4, whereas the Ki value for CMD was 3.2-fold higher. The influence of other genetic variations also differed between the two inhibitors. Docking simulations could explain the changes in the Ki values, based on the accessibility of TST and inhibitors to the heme moiety of the CYP3A4 molecule. In conclusion, the inhibitory effects of an inhibitor differ among CYP3A4 variants, suggesting that the genetic variation of CYP3A4 may contribute, at least in part, to interindividual differences in drug interactions mediated by CYP3A4 inhibition, and the pattern of the influences of genetic variation differs among inhibitors as well as substrates. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.

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下痢で薬の体内動態はどう変わる?.

大谷壽一.

薬局 (南山堂) 62(3) 378-383 2011.03

Single Work

未来先導型の研究と教育を目指して.

大谷壽一, 秋好健志.

薬剤学 (薬剤学) 70(4) 218-223 2010.07

Joint Work

代謝酵素が関係した相互作用パロキセチンとCYP2D6代謝薬剤.

大谷壽一.

薬局 (南山堂) 61(8) 2803-2807 2010.07

Single Work

併用禁忌・併用注意とは? どう決まる? どう判断する?.

大谷壽一, 佐藤宏樹, 澤田康文.

薬局 (南山堂) 61(8) 2767-2775 2010.07

Joint Work

類似名称による医薬品取り違え事故防止の試み.

玉木啓文, 堀里子, 佐藤宏樹, 三木晶子, 大谷壽一, 澤田康文.

日本病院薬剤師会雑誌 (日本病院薬剤師会) 46(6) 765-769 2010.06

Joint Work

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