Ohtani, Hisakazu



School of Medicine, Department of Clinical Pharmacy Division of Clinical Pharmacokinetics (Shinanomachi)



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Message from the Faculty Member 【 Display / hide

  • 医療薬学や臨床薬物動態学の楽しさを知っていただければと思います。

Profile Summary 【 Display / hide

  • 物理薬剤学や生物薬剤学、生化学、薬理学といった基礎薬学から、ヒトにおける臨床試験、患者や医療従事者を対象とした調査、疫学的調査、 医薬品情報、ファーマコメトリクス、IT技術にいたるさまざまな薬学領域の研究手法を活用することにより、おもに市販後の医薬品に関して、臨床的な問題点を解明し、適正かつ有効に使用するための 情報をつくるための研究を行っています。 具体的には、以下のような領域の研究を展開しています。 (1) 薬物の代謝過程やそこでの薬物相互作用の解析とテーラーメード医療への応用 (2) 消化管吸収過程における薬物相互作用の定量的予測 (3) 副作用軽減を目指した投与設計のための in vivo薬物動態・動力学的研究 (4) IT技術やファーマコメトリクスの活用による薬物治療の最適化

Other Affiliation 【 Display / hide

  • Keio University Hospital, Department of Pharmacy, Director

  • Faculty of Pharmacy, Department of Clinical Pharmacokinetics, Concurrently appointed professor

Career 【 Display / hide

  • 1994.04

    Research Associate, Pharmacist, The University of Tokyo Hospital

  • 1999.01

    Ohtani Estate Co., Ltd.

  • 1999.11

    Kyushu University, Graduate School of Pharmaceutical Sciences, Associate Professor

  • 2005.04

    Associate Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo

  • 2008.04

    Adjunct Associate Professor, Graduate School of Interdisciplinary Information Studies The University of Tokyo

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Academic Background 【 Display / hide

  • 1986.04

    The University of Tokyo, Faculty of Pharmaceutical Science, 薬学科

    University, Graduated

  • 1990.04

    The University of Tokyo, Graduate School of Pharmaceutical Sciences

    Graduate School, Completed, Master's course

Academic Degrees 【 Display / hide

  • 博士 (薬学) Ph.D. (Pharmacy), The University of Tokyo, Dissertation, 1999.05

Licenses and Qualifications 【 Display / hide

  • Pharmacist, 1990.05

  • JSPHCS-Certified Pharmacist, 2003.01

  • Certified National Tour Guide-Interpreter (English), 2016.02

  • 第一種放射線取扱主任者, (2010/10/28 試験合格), 2018.06

  • Hazardous Materials Engineer (Class A), 1990.07

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Research Areas 【 Display / hide

  • Medical pharmacy (Clinical Pharmaceutical Science)

  • Applied pharmacology (Applied Pharmacology)

Research Keywords 【 Display / hide

  • pharmacometrics

  • personalized medication

  • interindividual variation of pharmacokinetics

  • drug interactions


Books 【 Display / hide

  • The Manga Guide to Pharmacokinetics

    OHTANI Hisakazu, Ohmusha, Co., Ltd., 2021.05,  Page: 181

  • 臨床検査データブック 2019-2020.

    高久 史麿(監修), 黒川 清, 春日 雅人, 北村 聖(編集), 大谷 壽一 ほか 執筆., 医学書院, 東京, 2019.01

  • 臨床検査データブック 2017-2018.

    高久 史麿(監修), 黒川 清, 春日 雅人, 北村 聖(編集), 大谷 壽一 ほか 執筆., 医学書院, 東京, 2017.01

  • 解消!ポリファーマシー 上手なくすりの減らし方

    OHTANI Hisakazu, じほう, 2016.08

    Scope: pp 219-243

  • MRテキストI, 医薬品情報2012 (2015年改訂)

    大谷壽一, 岡淳一郎, 折井孝男(編), 大谷壽一, 秋好健志, 他執筆., 南山堂, 東京, 2015

    Scope: 80-129

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Papers 【 Display / hide

  • Time-dependent inhibition of CYP3A4-mediated midazolam metabolism by macrolide antibiotics in CYP3A4 genetic variants: Comparison with testosterone metabolism

    Akiyoshi Takeshi, Naitou Rina, Imaoka Ayuko, Miyazaki Mitsue, Guengerich F. Peter, Nakamura Katsunori, Yamamoto Koujiro, Ohtani Hisakazu


    ISSN  0946-1965

  • Dual kinetics of OATP2B1: Inhibitory potency and pH-dependence of OATP2B1 inhibitors

    Sato R., Akiyoshi T., Morita T., Katayama K., Yajima K., Kataoka H., Imaoka A., Ohtani H.

    Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  41   100416 2021.12

    ISSN  13474367

     View Summary

    Organic anion transporting polypeptide (OATP) 2B1 is expressed in the intestine and liver, and OATP2B1-mediated transport of estrone 3-sulfate is pH-dependent and consists of: the high-affinity component (Hc) and low-affinity component (Lc). This study aimed to evaluate the influence of pH on the transport kinetics of each component, along with the inhibitory nature of ten OATP2B1 inhibitors. The Michaelis constants (Km) were 4-fold and 1.5-fold lower at pH 6.3 than at pH 7.4, for Hc and Lc respectively. The inhibitory potencies of diclofenac, indomethacin, and ibuprofen towards Hc were 1.5–4.3 fold lower at pH 6.3 than at pH 7.4. Contrastingly, inhibitory potencies towards Lc were 9.0–52 fold lower at pH 7.4. Similarly, the inhibitory effect of naproxen was stronger towards Hc at pH 6.3 and towards Lc at pH 7.4. On the other hand, celecoxib selectively inhibited Lc transport at pH 7.4. Rifampicin inhibited both components at pH 6.3 and 7.4 to a similar extent, while bromosulphophthalein, naringin, and gefitinib selectively inhibited Hc irrespective of pH. Fexofenadine inhibited neither component. In conclusion, the transport affinities of both Hc and Lc were enhanced under acidic conditions. The influence of pH on the inhibitory potency towards each component varied among the inhibitors.

  • Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage

    Tsuchitani Toshiaki, Akiyoshi Takeshi, Imaoka Ayuko, Ohtani Hisakazu


    ISSN  2055-0294

  • Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants

    Yamaguchi Y., Akiyoshi T., Kawamura G., Imaoka A., Miyazaki M., Guengerich F.P., Nakamura K., Yamamoto K., Ohtani H.

    Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  38   100384 2021.06

    ISSN  13474367

     View Summary

    Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals inhibit CYP3A4 to cause clinically significant drug-drug interactions. In the present quantitative study, we investigated the inhibitory effects of three azole antifungals (ketoconazole, voriconazole, and fluconazole) on testosterone metabolism by recombinant CYP3A4 genetic variants (CYP3A4.1 (WT), CYP3A4.2, CYP3A4.7, CYP3A4.16, and CYP3A4.18) and compared them with those previously reported for itraconazole. The inhibition constants (Ki) of ketoconazole, voriconazole, and fluconazole for rCYP3A4.1 were 3.6 nM, 3.2 μM, and 16.1 μM, respectively. The Ki values of these azoles for rCYP3A4.16 were 13.9-, 13.6-, and 6.2-fold higher than those for rCYP3A4.1, respectively, whereas the Ki value of itraconazole for rCYP3A4.16 was 0.54-fold of that for rCYP3A4.1. The other genetic variants had similar effects on the Ki values of the three azoles, whereas a very different pattern was seen for itraconazole. In conclusion, itraconazole has unique characteristics that are distinct from those shared by the other azole anti-fungal drugs ketoconazole, voriconazole, and fluconazole with regard to the influence of genetic variations on the inhibition of CYP3A4.

  • Estimation of absolute oral bioavailability without performing an intravenous clinical study

    Ohtani H., Iwata R., Imaoka A., Akiyoshi T.

    Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  38   100392 2021.06

    ISSN  13474367

     View Summary

    The absolute oral bioavailability (BA) of drugs are yet to be determined, and intravenous pharmacokinetic studies are currently considered indispensable for determining the BA values of oral drugs. The aim of this study was to develop and validate a novel approach to estimating BA values without intravenous pharmacokinetic data. Based on the drug inclusion criteria, such as exhibiting a urinary recovery rate of (Ru) of ≥20% in a clinical study, 13 drugs were included in the present study, and pharmacokinetic data for them were collected from the literature. The fraction excreted unchanged into urine (fe) was calculated for healthy subjects by dividing the Ru value by the total recovery rate. The contribution of renal excretion to total clearance from the systemic circulation (Rren) was estimated by subjecting oral clearance and creatinine clearance to regression in subjects with normal and impaired renal function. BA was estimated as fe/Rren and compared with the observed BA (BAobs). The predicted BA values for 9 drugs fell within ±20% of their BAobs. The examined approach makes it possible to estimate BA values for drugs with mean renal excretion values in healthy subjects and oral clearance in subjects with various renal function, without intravenous pharmacokinetic data.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • Correction to: Novel method to estimate the appropriate dosing interval for activated charcoal to avoid interaction with other drugs (European Journal of Clinical Pharmacology, (2020), 76, 11, (1529-1536), 10.1007/s00228-020-02931-y)

    Ohtani H., Nakamura K., Imaoka A., Akiyoshi T.

    European Journal of Clinical Pharmacology (European Journal of Clinical Pharmacology)  76 ( 11 ) 1537 - 1537 2020.11

    ISSN  00316970

     View Summary

    © 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Figure 3 image was inadvertently removed from the original article. The original article has been corrected.

  • 医薬品の第三者への転売・譲渡の違法性に関する消費者の意識調査

    藤井 萌未, 今岡 鮎子, 秋好 健志, 望月 眞弓, 山浦 克典, 大谷 壽一

    日本医薬品情報学会総会・学術大会講演要旨集 ((一社)日本医薬品情報学会)  20回   201 - 201 2017.06

  • CYP3A4 genetic variantsに対する各種アゾール系抗真菌薬の阻害特性の比較

    川村 豪, 今岡 鮎子, 秋好 健志, 日比野 英幸, 荒木 拓也, 宮崎 光江, Guengerich F.P., 中村 克徳, 中村 智徳, 山本 康次郎, 大谷 壽一

    日本薬学会年会要旨集 ((公社)日本薬学会)  137年会 ( 4 ) 191 - 191 2017.03

    ISSN  0918-9823

  • インターネットオークションにおける無承認無許可医薬品の取引実態

    藤井 萌未, 今岡 鮎子, 秋好 健志, 大谷 壽一

    日本薬学会年会要旨集 ((公社)日本薬学会)  137年会 ( 4 ) 118 - 118 2017.03

    ISSN  0918-9823

  • イリノテカン誘発性消化管障害時におけるダビガトランの吸収動態変動とその要因

    服部 智貴, 今岡 鮎子, 秋好 健志, 大谷 壽一

    日本薬学会年会要旨集 ((公社)日本薬学会)  137年会 ( 4 ) 66 - 66 2017.03

    ISSN  0918-9823

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Presentations 【 Display / hide

  • Pharmacy education in Japan - Clinical rotation and preceptorship -

    OHTANI Hisakazu

    Seminar National. Asosiasi Pendidikan Tinggi Farmasi Indonesia (APTFI) II (Banjarmasin, Indonesia) , 2017.11, Oral Presentation(guest/special), Association of Indonesian Pharmacy Higher Education (APTFI)

  • 医療連携で薬剤師に求められる臨床薬物動態学の基本

    OHTANI Hisakazu

    日本薬学会関東支部 薬剤師向け研修講演会 (前橋) , 2017.10, Public discourse, seminar, tutorial, course, lecture and others, 日本薬学会関東支部


  • 受理される論文・されない論文

    OHTANI Hisakazu

    第1回 医療薬学教育セミナー (東京) , 2017.04, Public discourse, seminar, tutorial, course, lecture and others, 日本医療薬学会

  • イリノテカン誘発性消化管障害時におけるダビガトランの吸収動態変動とその要因

    HATTORI Tomoki, IMAOKA Ayuko, AKIYOSHI Takeshi, OHTANI Hisakazu

    日本薬学会第 137 年会 (仙台) , 2017.03, Oral Presentation(general)

  • グレープフルーツジュース成分および resveratrol の CYP2C9 阻害特性解析

    UCHIYAMA Marika, AKIYOSHI Takeshi, IMAOKA Ayuko, OHTANI Hisakazu

    日本薬学会第 137 年会 (仙台) , 2017.03, Poster (general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • CYP2Cs及びOATPsを介した薬物ー飲食物間相互作用とその個人差の定量的解明


    日本学術振興会, Grant-in-Aid for Scientific Research, 大谷壽一, Research grant, Principal Investigator

  • Analysis of the inter-individual variations of food-drug interactions via CYP2Cs and OATPs


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 大谷 壽一, Grant-in-Aid for Scientific Research (C), Principal Investigator

     View Summary

    本研究では、CYP2C9, CYP2C19, OATP1A2, OATP2B1 を介した相互作用に個人差をもたらす遺伝的要因を定量的に解明することを目的に、これらの遺伝的バリアント (アミノ酸変異を伴うもの) の代謝/輸送活性に対する各種飲食物成分の阻害特性を定量的に評価することを目的としている。
    本年度は、まずCYP2C9についてCYP2C9.1, .2, .3 の3種のバリアントにおいて、代謝活性に対する飲食物成分(レスベラトロール及びセサミン)の阻害特性を比較検討した。その結果、セサミンはいずれのバリアントに対しても時間依存的阻害を示したが、その阻害強度 (kinact/KI) はバリアント間で大きく異なった。一方、興味深いことにレスベラトロールはCYP2C9.2に対してのみ時間依存的阻害を示した。
    OATPs に関しては、天然果汁由来OATP1A2阻害成分として、ナリンギン、ナリンゲニンに加えて、かんきつ果汁から、強い阻害作用を有するナリルチンを同定し、その阻害特性を解析し、学会発表した。また、OATP2B1については、クランベリーに強い阻害作用を有するか区分を見出し、現在、その単離同定を進めている。
    研究対象としているCYP2C9, CYP2C19, OATP1A2, OATP2B1 について、それぞれの遺伝的バリアントの機能を評価する系が順調に確立稼働し、各種飲食物の影響が順次定量的に評価されている。そして、飲食物から新たな阻害成分 (ナリルチン) を発見することもできた。また、研究1年目の成果については、国際学会や国際誌にその成果が発表された。今後も学会発表も継続される予定である。
    今後は、飲食物由来の各種阻害剤について阻害様式の評価や阻害特性の定量的評価を行うとともに、さまざまな飲食物について広くサーチし、新たな阻害成分の同定につとめる。併せて、バリアント間での阻害様式の差異や、それをもたらす機構についても解明を進めていきたい。また、得られた成果をもとに、薬物-飲食物間相互作用の臨床的インパクトを評価するための IVIVE (in vitro-to-in vivo extrapolation) についても実施する予定である。

  • 薬物−飲食物間相互作用の強度に個人差をもたらす遺伝的要因の解明


    日本学術振興会, Grant-in-Aid for Scientific Research, 大谷壽一, Principal Investigator

  • Quantitative analysis of the factors that confer inter-individual variation of the extent of beverage-drug interactions


    MEXT,JSPS, Grant-in-Aid for Scientific Research, Hisakazu OHTANI, AKIYOSHI Takeshi, IMAOKA Ayuko, Grant-in-Aid for Scientific Research (C), Principal Investigator

     View Summary

    The influences of genetic variation of CYP3A4 on the inhibitory kinetics of its inhibitors varied among the inhibitors and affected by the probe substrate used. The inhibitor manners (patterns) of metabolic inhibitors contained in fruit juice are different among CYP isoforms, i.e. CYP3A4, 2C9 and 2C19. The research should be focused upon the mode of inhibition that is clinically most relevant.
    Using newly developed cell lines stably expressing a transporter OATP1A2 or OATP2B1, some unidentified inhibitory ingredient(s) for these transporters are considered to be contained in some fractions of grapefruit juice.

  • Quantitative analysis of genetic factors affecting the extent of drug interactions via mechanism based inhibition of cytochrome P450


    Keio University, Grant-in-Aid for Scientific Research, Hisakazu Ohtani, YAMAMOTO Koujirou, AKIYOSHI Takeshi, YAMAZAKI Hiroshi, Grant-in-Aid for Scientific Research (C), Research grant, Principal Investigator

     View Summary

    There seems to be considerable inter-individual variations in the extent of drug interactions, especially via the inhibition of oxidative metabolic enzymes, P450s. This study aimed to investigate quantitatively the influence of genetic variation of P450s, such as CYP3A4 and CYP2D6, on the extent of drug interaction in the in vitro studies using genetic variants. As a result of enzymatic study with probe substrates and mechanism-based inhibitors (MBI), we concluded that the inhibitory potencies of MBI differ among genetic variants. These results suggest that the genetic variation of metabolic enzymes affect the extent of drug interactions caused by their inhibitors, as well as the pharmacokinetics of their substrate drugs.

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Awards 【 Display / hide

  • 年会優秀発表賞

    "丹羽しおり, 秋好健志, 今岡鮎子, 大谷壽一.", 2014.03, 日本薬学会第134年会, In vitro データをもとにした、CYP2D6 variants における paroxetine の非線型体内動態の予測.

  • 最優秀ポスター賞

    "三井梨恵子, 秋好健志, 今岡鮎子, 大谷壽一.", 2013.08, 医薬品情報学会 (第16回日本医薬品情報学会総会・学術大会), 免疫抑制剤、βblocker、ステロイドの低用量域における全身性副作用の用量依存性評価.

  • 優秀発表賞

    "○青野いづみ, 桑原亜記, 今井奈津美, 剱田侑希, 手塚淑人, 門田佳子, 小林典子, 鈴木小夜, 大谷壽一, 佐伯晴子, 木津純子.", 2013.03, 日本薬学会第133年会, 学生主体で構築した新たな服薬指導事前実習の評価.

  • 優秀ポスター賞

    "秋好健志, 齊藤隆志, 村瀬沙織, 宮崎光江, 中村克徳, 中村智徳, Guengerich F, Peter, 山本康次郎, 大谷壽一.", 2010.07, 医療薬学フォーラム2010/第18回クリニカルファーマシーシンポジウム, CYP3A4 変異型分子種の代謝活性に対する阻害剤の阻害強度の比較.

  • 日本医療薬学会奨励賞

    2007.09, 日本医療薬学会, 薬物動態・動力学の活用によるテーラーメイド処方設計支援システムの基盤技術の確立

    Country: 日本


Courses Taught 【 Display / hide











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Courses Previously Taught 【 Display / hide

  • 薬学への招待

    Keio University, 2015, Spring Semester, Major subject, Lecture

  • C16(2)剤形をつくる

    Keio University, 2015, Autumn Semester, Major subject, Lecture

  • C15(3)テーラーメイド薬物治療を目指して

    Keio University, 2015, Spring Semester, Major subject, Lecture, Within own faculty

  • 臨床物理薬剤・製剤学

    Keio University, 2015, Spring Semester, Major subject, Lecture

  • 老年薬学と在宅医療

    Keio University, 2015, Autumn Semester, Lecture

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Educational Activities and Special Notes 【 Display / hide

  • 第3回アジア薬科大学連合 Deans Forum "Regional Harmonization of Pharmacy Education in Asia" (組織委員・座長・ポスター発表)


    , Lecture at Education Method and Practice


Social Activities 【 Display / hide

  • JGSDF (Japanese Army) Reserve


     View Summary

    Reserve Major (Pharmacy Officer)

Memberships in Academic Societies 【 Display / hide

  • The Pharmaceutical Society of Japan, 

  • 日本医療薬学会, 

  • Japanese Society of Drug Informatics (JASDI)

  • 日本薬理学会


Committee Experiences 【 Display / hide

  • 2019.02

    臨時委員, 薬事・食品衛生審議会

     View Remarks


  • 2011.04

    Committee Member, Pharmacist License Examination Committee

  • 2009.05

    Expert Committee Member, Pharmaceuticals and Medical Devices Agency

  • 2013.02

    代議員, 日本薬学会

  • 2012.04

    Editor, The Pharmaceutical Society of Japan

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