Ohtani, Hisakazu

写真a

Affiliation

School of Medicine, Department of Clinical Pharmacy (Shinanomachi)

Position

Professor

Related Websites

External Links

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 Pharmacy, Concurrently appointed professor

Career 【 Display / hide

  • 1994.04
    -
    1999.01

    Research Associate, Pharmacist, The University of Tokyo Hospital

  • 1999.01
    -
    1999.10

    Ohtani Estate Co., Ltd.

  • 1999.11
    -
    2005.03

    Kyushu University, Graduate School of Pharmaceutical Sciences, Associate Professor

  • 2005.04
    -
    2009.03

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

  • 2008.04
    -
    2009.03

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

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Academic Background 【 Display / hide

  • 1986.04
    -
    1990.03

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

    University, Graduated

  • 1990.04
    -
    1992.03

    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

  • Life Science / Clinical pharmacy (Clinical Pharmaceutical Science)

  • Life Science / Pharmacology (Applied Pharmacology)

Research Keywords 【 Display / hide

  • pharmacometrics

  • personalized medication

  • interindividual variation of pharmacokinetics

  • drug interactions

 

Books 【 Display / hide

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Papers 【 Display / hide

  • Determination of single-molecule transport activity of OATP2B1 by measuring the number of transporter molecules using electrophysiological approach

    Yajima K., Akiyoshi T., Sakamoto K., Suzuki Y., Oka T., Imaoka A., Yamamura H., Kurokawa J., Ohtani H.

    Journal of Pharmacological Sciences (Journal of Pharmacological Sciences)  153 ( 3 ) 153 - 160 2023.11

    ISSN  13478613

     View Summary

    Transporter-mediated clearance is determined by two factors, its single-molecule clearance, and expression level. However, no reliable method has been developed to evaluate them separately. This study aimed to develop a reliable method for evaluating the single-molecule activity of membrane transporters, such as organic anion transporting polypeptide (OATP) 2B1. HEK293 cells that co-expressed large conductance calcium-activated potassium (BK) channel and OATP2B1 were established and used for the following experiments. i) BK channel-mediated whole-cell conductance was measured using patch-clamp technique and divided by its unitary conductance to estimate the number of channels on plasma membrane (QI). ii) Using plasma membrane fraction, quantitative targeted absolute proteomics determined the stoichiometric ratio (ρ) of OATP2B1 to BK channel. iii) The uptake of estrone 3-sulfate was evaluated to calculate the Michaelis constant and uptake clearance (CL) per cell. Single-molecule clearance (CLint) was calculated by dividing CL by QI·ρ. QI and ρ values were estimated to be 916 and 2.16, respectively, yielding CLint of 5.23 fL/min/molecule. We successfully developed a novel method to reliably measure the single-molecule activity of a transporter, which could be used to evaluate the influences of factors such as genetic variations and post-translational modifications on the intrinsic activity of transporters.

  • Irinotecan-induced gastrointestinal damage alters the expression of peptide transporter 1 and absorption of cephalexin in rats

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

    Biopharmaceutics and Drug Disposition (Biopharmaceutics and Drug Disposition)  44 ( 5 ) 372 - 379 2023.10

    ISSN  01422782

     View Summary

    Irinotecan causes severe gastrointestinal damage, which may affect the expression of intestinal transporters. However, neither the expression of peptide transporter 1 (Pept1) nor the pharmacokinetics of Pept1 substrate drugs has been investigated under irinotecan-induced gastrointestinal damage. Therefore, the present study quantitatively investigated the effects of irinotecan-induced gastrointestinal damage on the intestinal expression of Pept1 and absorption of cephalexin (CEX), a typical Pept1 substrate, in rats. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. The expression of Pept1 mRNA and the Pept1 protein in the upper, middle, and lower segments of the small intestine of irinotecan-treated rats was assessed by quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. The pharmacokinetic profile of CEX was examined after its oral or intravenous administration (10 mg/kg). In irinotecan-treated rats, ∼2-fold increases in Pept1 protein levels were observed in all three segments, whereas mRNA levels remained unchanged. The oral bioavailability of CEX significantly decreased to 76% of that in control rats. The decrease in passive diffusion caused by intestinal damage may have overcome the increase in Pept1-mediated uptake. In conclusion, irinotecan may decrease the intestinal absorption of Pept1 substrate drugs; however, it increased the expression of intestinal Pept1.

  • 多発性骨髄腫患者におけるダラツムマブ皮下投与時の有害事象に対するジフェンヒドラミンとレボセチリジン前処置の比較

    末廣 直哉, 長島 彩乃, 西川 はる, 鈴川 真由, 櫻井 洋臣, 村松 博, 青森 達, 大谷 壽一

    医療薬学 ((一社)日本医療薬学会)  49 ( 8 ) 303 - 309 2023.08

    ISSN  1346-342X

     View Summary

    当院で2021年8月~2022年7月に多発性骨髄腫に対してダラツムマブ皮下投与を新規に開始した患者31例を対象とし、前処置薬にジフェンヒドラミンを使用した群(7例)とレボセチリジンを使用した群(24例)に分け、Infusion reaction(IR)の発現頻度と、治療後の眠気の発現頻度を群間比較した。IRの発現は両群とも認めなかった。眠気はジフェンヒドラミン群の2例(29%)、レボセチリジン群の1例(4例)に認め、ジフェンヒドラミン群で頻度が高い傾向にあった。

  • The influence of temperature on the metabolic activity of CYP2C9, CYP2C19, and CYP3A4 genetic variants in vitro

    Kojima M., Machida K., Cho S., Watanabe D., Seki H., Shimoji M., Imaoka A., Yamazaki H., Guengerich F.P., Nakamura K., Yamamoto K., Akiyoshi T., Ohtani H.

    Xenobiotica (Xenobiotica)  53 ( 5 ) 357 - 365 2023

    ISSN  00498254

     View Summary

    1. Temperature is considered to affect the activity of drug-metabolizing enzymes; however, no previous studies have compared temperature dependency among cytochrome P450 genetic variants. This study aimed to analyse warfarin 7-hydroxylation by CYP2C9 variants; omeprazole 5-hydroxylation by CYP2C19 variants; and midazolam 1-hydroxylation by CYP3A4 variants at 34 °C, 37 °C, and 40 °C. 2. Compared with that seen at 37 °C, the intrinsic clearance rates (V max/K m) of CYP2C9.1 and.2 were decreased (76 ∼ 82%), while that of CYP2C9.3 was unchanged at 34 °C. At 40 °C, CYP2C9.1,.2, and.3 exhibited increased (121%), unchanged and decreased (87%) intrinsic clearance rates, respectively. At 34 °C, the clearance rates of CYP2C19.1A and.10 were decreased (71 ∼ 86%), that of CYP2C19.1B was unchanged, and those of CYP2C19.8 and.23 were increased (130 ∼ 134%). At 40 °C, the clearance rates of CYP2C19.1A,.1B,.10, and.23 remained unaffected, while that of CYP2C19.8 was decreased (74%). At 34 °C, the clearance rates of CYP3A4.1 and.16 were decreased (79 ∼ 84%), those of CYP3A4.2 and.7 were unchanged, and that of CYP3A4.18 was slightly increased (112%). At 40 °C, the clearance rate of CYP3A4.1 remained unaffected, while those of CYP3A4.2,.7,.16, and.18 were decreased (58 ∼ 82%). 3. These findings may be clinically useful for dose optimisation in patients with hypothermia or hyperthermia.

  • Comparison of the transport kinetics of fexofenadine and its pH dependency among OATP1A2 genetic variants

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

    Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  47   100470 2022.12

    Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  13474367

     View Summary

    Little is known about the influence of non-synonymous genetic variations in the organic anion-transporting polypeptide (OATP) 1A2 on the transport kinetics of its substrate fexofenadine. Moreover, the pH-dependency of fexofenadine uptake also remains unclear. This study aimed to evaluate the effects of genetic variants (Ile13Thr, Asn128Tyr, Glu172Asp, Ala187Thr, and Thr668Ser) on the OATP1A2-mediated uptake of fexofenadine at pH 6.3 and 7.4 and compare the pH dependency of OATP1A2-mediated uptake of fexofenadine and estrone 3-sulfate. The uptake clearances of 0.3 μM and 300 μM fexofenadine were compared with those of 0.3 μM and 300 μM estrone 3-sulfate at pH 6.3 and 7.4. Among the six variants examined, the Thr668Ser variant showed the highest fexofenadine uptake clearance (Vmax/Km); i.e., 4.53- and 6.28-fold higher uptake clearance than the wild type at pH 6.3 and 7.4, respectively. All variants exhibited significantly higher fexofenadine uptake at pH 6.3 than at pH 7.4. Compared with estrone 3-sulfate uptake, the uptake of 0.3 μM fexofenadine was less sensitive to pH. Our findings suggest that genetic variations in OATP1A2 may lead to altered intestinal absorption of fexofenadine, such as increased absorption in subjects bearing the Thr668Ser variant, which showed higher uptake activity.

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

Reviews, Commentaries, etc. 【 Display / hide

  • 骨髄腫の薬物治療の留意点 薬物動態と薬物相互作用の視点から(Pharmacokinetic aspects of drugs used for the treatment of myeloma)

    大谷 壽一

    International Journal of Myeloma ((一社)日本骨髄腫学会)  13 ( 3 ) 95 - 95 2023.05

  • 薬物相互作用の科学的評価とpersonalized medicationへの応用

    大谷 壽一

    TDM研究 ((一社)日本TDM学会)  39 ( 2 ) 38 - 38 2022.05

    ISSN  0911-1026

  • MeDaCaアプリを活用した妊娠・授乳と薬相談 オンライン相談の取り組み

    櫻井 しおり, 三浦 あす美, 鈴木 靖奈, 小谷 宙, 清宮 啓介, 村松 博, 青森 達, 大谷 壽一

    日本薬学会年会要旨集 ((公社)日本薬学会)  142年会   27PO1 - pm2 2022.03

    ISSN  0918-9823

  • OATP1A2 variantsの輸送活性に対する温度の影響

    片岡 寛樹, 冬木 陽大, 秋好 健志, 森田 時生, 矢島 広大, 今岡 鮎子, 片山 和浩, 大谷 壽一

    日本薬学会年会要旨集 ((公社)日本薬学会)  142年会   27PO6 - am1 2022.03

    ISSN  0918-9823

  • 消化管吸収過程におけるP糖蛋白質を介した薬物相互作用のin vitro ATPase活性からの予測

    土谷 聡耀, 秋好 健志, 今岡 鮎子, 大谷 壽一

    日本薬学会年会要旨集 ((公社)日本薬学会)  142年会   27PO5 - am2 2022.03

    ISSN  0918-9823

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Presentations 【 Display / hide

  • Drug-beverage interaction

    Hisakazu Ohtani

    29th Dubai International Pharmaceutical & Technologies Conference & Exhibition - DUPHAT (Dubai) , 

    2023.01

    Oral presentation (invited, special)

  • 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 (invited, 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 lecture, seminar, tutorial, course, or other speech, 日本薬学会関東支部

    yakuzaishi2017.pdf

  • 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 lecture, seminar, tutorial, course, or other speech, 日本医療薬学会

  • フェノバルビタールと活性炭の相互作用は食事により減弱する

    IMAOKA Ayuko, OGATA Yuka, AKIYOSHI Takeshi, OHTANI Hisakazu

    日本薬学会第 137 年会 (仙台) , 

    2017.03

    Oral presentation (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

    2018.04
    -
    2021.03

    日本学術振興会, Grant-in-Aid for Scientific Research, Research grant, Principal investigator

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

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Ohtani Hisakazu, Grant-in-Aid for Scientific Research (C), Principal investigator

     View Summary

    The mechanism of food-drug interactions includes the inhibition of metabolic enzymes or drug transporters, which have genetic variations. The aim of this study is to clarify whether the genetic variations of metabolic enzymes and transporters lead to the altered inhibitory kinetics of respective inhibitors contained in a variety of fruit juices. We focused upon two metabolic enzymes (CYP2C9 and CYP2C19) and two transporters (OATP1A2 and OATP2B1). Detailed analysis revealed that the inhibitory kinetics of various inhibitors highly differ among genetic variants. Therefore, the genetic variants of metabolic enzymes and drug transporters are considered to be one of the important factors to confer inter-individual variation in the extent of food-drug interactions. We also succeeded in identifying a novel OATP inhibitor, narirutin, from grape fruit juice.

  • 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

    2015.04
    -
    2018.03

    日本学術振興会, Grant-in-Aid for Scientific Research, Principal investigator

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

    2015.04
    -
    2018.03

    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

    2012.04
    -
    2015.03

    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

  • 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

  • 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.

 

Courses Taught 【 Display / hide

  • STUDY OF MAJOR FIELD: (CLINICAL PHARMACY)

    2023

  • SEMINAR:(CLINICAL PHARMACY)

    2023

  • RESEARCH FOR BACHELOR'S THESIS 1

    2023

  • PRIOR LEARNING FOR CLINICAL PRACTICE 2

    2023

  • PHARMACOLOGY FOR NURSING AND HEALTH CARE

    2023

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Courses Previously Taught 【 Display / hide

  • 薬学への招待

    Keio University

    2015.04
    -
    2016.03

    Spring Semester, Lecture

  • C16(2)剤形をつくる

    Keio University

    2015.04
    -
    2016.03

    Autumn Semester, Lecture

  • C15(3)テーラーメイド薬物治療を目指して

    Keio University

    2015.04
    -
    2016.03

    Spring Semester, Lecture, Within own faculty

  • 臨床物理薬剤・製剤学

    Keio University

    2015.04
    -
    2016.03

    Spring Semester, Lecture

  • 老年薬学と在宅医療

    Keio University

    2015.04
    -
    2016.03

    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)

    2014.06

    , Lecture at Education Method and Practice

 

Social Activities 【 Display / hide

  • JGSDF (Japanese Army) Reserve

    2011.11
    -
    Present

     View Summary

    Reserve Lieutenant Colonel (Pharmacy Officer)

Media Coverage 【 Display / hide

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Memberships in Academic Societies 【 Display / hide

  • The Pharmaceutical Society of Japan, 

    1990
    -
    Present
  • 日本医療薬学会, 

    1997
    -
    Present
  • Japanese Society of Drug Informatics (JASDI)

     
  • 日本薬理学会

     

Committee Experiences 【 Display / hide

  • 2023.10
    -
    2029.09

    Associate Member, Science Council of Japan

  • 2019.02
    -
    Present

    臨時委員, 薬事・食品衛生審議会

     View Remarks

    医薬品第一部会

  • 2009.05
    -
    Present

    Expert Committee Member, Pharmaceuticals and Medical Devices Agency

  • 2010.04
    -
    Present

    学術評議員, 日本薬理学会

  • 2009.04
    -
    Present

    Examination Committee Member, MR Education & Accreditation Center of Japan

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