Akiyoshi, Takeshi

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy Department of Clinical pharmacokinetics ( Shiba-Kyoritsu )

Position

Associate Professor

Related Websites

Contact Address

医学部_東京都新宿区信濃町35 総合医科学研究棟 4 階 4S7教室, 薬学部_東京都港区芝公園1-5-30

Profile Summary 【 Display / hide 】

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Academic Degrees 【 Display / hide 】

  • Ph.D.(Pharmacy), Fukuoka University, Dissertation, 2008.03

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Licenses and Qualifications 【 Display / hide 】

  • 薬剤師, 2001.05

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Research Areas 【 Display / hide 】

  • Life Science / Clinical pharmacy (Clinical pharmacokinetics)

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Research Keywords 【 Display / hide 】

  • Genetic variation・Epigeneitcs

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Research Themes 【 Display / hide 】

  • Pharmacokinetics Pharmacodynamics/Drug interaction, Polymorphism／Epigenetics, 

    2008
    -
    Present

    　View Summary

    In order to optimize the medication based on the background of each patient, a variety of research for dosage adjustment using genetic information is in progress. However our understanding for individual variations of the efficacy and adverse reactions of medicines still remains to be further investigated. My research topics are the evaluation of the biological factors which affect the pharmacokinetics (and pharmacodynamics) and the extent of drug-drug interactions (DDI) as follows,
    (1) The effects of genetic and epigenetic factors on inter-individual differences of the protein expression and function of the metabolic enzyme and transporters
    The aim of this research topic is to evaluate the contribution of genetic and/or epigenetic factors such genetic polymorphism for cytochromeP450 enzyme and transporter and epigenetic regulation by microRNA etc on pharmacokinetic profiles certain drugs.

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Books 【 Display / hide 】

  • MRテキスト2018, 医薬品情報.

    大谷壽一(編), 大谷壽一, 秋好健志., 南山堂, 東京, 2018.01

    Scope: 16-38

  • MRテキストI, 医薬品情報2012. 2015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: 80-109

  • MRテキストI, 医薬品情報2012.

    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, 2012.01

    Scope: 80-129

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Papers 【 Display / hide 】

  • Stoichiometric transport of estrone 3-sulfate among genetic variants of OATP1A2 and OATP2B1 and structural analysis by molecular dynamics simulation: Impairment of gating mechanism in the unstable inward-open conformation of OATP2B1 (Asp215Val) significantly suppress the transport activity.

    Akiyoshi T, Tonduru AK, Kataoka H, Morita T, Yajima K, Imaoka A, Katayama K, Medarametla P, Uchida Y, Poso A, Ohtani H, Terasaki T

    Drug metabolism and disposition: the biological fate of chemicals 53 ( 12 ) 100198 2025.11

    Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  0090-9556

    　View Summary

    This study investigated the impact of genetic variations in organic anion transporting polypeptides (OATPs) 1A2 and 2B1 on their transport activity at pH 6.3 and 7.4 by using HEK293 cells expressing OATP variants, focusing on stoichiometric transport kinetic parameters corrected for the number of transporters on the plasma membrane. In the OATP2B1 Asp215Val, the maximal velocity per OATP molecule and intrinsic clearance at pH 6.3 were drastically reduced to 0.0648- and 0.0178-fold, respectively, compared with the wild type. All tested OATP1A2 variants exhibited increased transport activity at pH 6.3, suggesting that OATP1A2 is more sensitive to extracellular pH. Furthermore, we used the AlphaFold model to explain the observed differences in transport activity among genetic variants. In OATP1A2, the Glu172Asp mutation replaces a longer glutamate side chain with a shorter aspartate, which may enhance substrate interactions while weakening the salt-bridge interactions with neighboring residues, potentially compromising structural integrity. In OATP2B1, the Asp215Val variant was found to disrupt a key salt-bridge interaction with Lys595, which destabilizes the outward-open conformation. Moreover, the Val201Met mutation appears to lock the transporter in a single conformational state. Our findings underscore the importance of transmembrane helix 4 in maintaining functional conformational dynamics and suggest that mutations in this region can significantly alter substrate binding and transport efficiency in OATP1A2 and 2B1. Significance Statement: This study combined uptake assays using transporter-expressing cell lines, liquid chromatography–tandem mass spectrometry transporter quantification, and computer modeling to clarify the changes in transport activity per molecule, and these mechanisms caused by amino acid substitutions in organic anion transporting polypeptides 1A2 and 2B1.

  • Inhibition kinetics of citrus jabara juice and its components on CYP2C9 activity.

    Koinuma K, Morita T, Uekusa Y, Kikuchi H, Imaoka A, Akiyoshi T, Ohtani H

    Journal of pharmaceutical sciences 114 ( 11 ) 103983 2025.09

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0022-3549

    　View Summary

    Our previous studies demonstrated that the ethyl acetate extract of the juice of jabara (JEx), a Japanese citrus fruit, inhibited cytochrome P450 (CYP) 3A4 activity in a time-dependent manner, but does not inhibit CYP2C19 activity. Its components, 3,3′,4′,5,6,7,8-heptamethoxyflavone (HpMF) and 3,3′,4′,5,6,7-hexamethoxyflavone (HxMF), have been shown to be responsible for this CYP3A4 inhibition. This study aimed to investigate the nature of CYP2C9 inhibition by JEx, HpMF, and HxMF. The time-dependent inhibition kinetics of JEx against human recombinant CYP2C9 were investigated in vitro using warfarin as a substrate. The time-independent inhibition kinetics of JEx, HpMF, and HxMF against CYP2C9 were also determined. JEx did not cause time-dependent inhibition of CYP2C9, while JEx, HpMF, and HxMF inhibited CYP2C9 activity in a time-independent manner with IC<inf>50</inf> values of 2.65 % equivalent, 16.2 µM, and 57.8 µM, respectively. HpMF and HxMF were considered to be primarily responsible for CYP2C9 inhibition by JEx. The ingestion of 250 mL of jabara juice was estimated to reduce intestinal CYP2C9 activity to 3 % of the control value assuming of dilution with 210 mL of intestinal fluid, suggesting that jabara juice may cause food-drug interactions via intestinal CYP2C9 inhibition.

  • Comparative analysis of the single-molecule transport kinetics of OATP1B1 genetic variants.

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

    Journal of pharmacological sciences 158 ( 3 ) 166 - 171 2025.07

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  1347-8613

    　View Summary

    Several genetic variants of OATP1B1, a hepatic uptake transporter, increase the blood concentrations of substrate drugs, e.g., ∗15 carriers exhibit higher blood substrate concentrations than ∗1b carriers. It remains unclear whether these differences are due to changes in expression or intrinsic activity (transport activity per OATP1B1 molecule). This study compared the intrinsic activity of four OATP1B1 variants, ∗1a, ∗1b, ∗5, and ∗15, using HEK293 cell lines that co-expressed large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (BK) channels and one of the OATP1B1 variants. To estimate the kinetic parameters K<inf>m</inf> and V<inf>max</inf>, 2′, 7′-dichlorofluorescein uptake was evaluated. The number of OATP molecules per cell (Q<inf>T</inf>) was calculated from BK channel-mediated whole-cell conductance and the OATP1B1/BK channel expression ratio (ρ) (determined by LC-MS/MS). V<inf>max,int</inf> (maximum intrinsic transport velocity) was obtained by dividing V<inf>max</inf> by Q<inf>T</inf>, and intrinsic clearance (CL<inf>int</inf>) was calculated as V<inf>max,int</inf>/K<inf>m</inf>. The K<inf>m</inf> values of ∗1a, ∗1b, ∗5, and ∗15 were 12.5, 9.19, 7.53, and 10.4 μM, and their V<inf>max,int</inf> values were 3.0, 7.0, 1.5, and 1.2 × 10<sup>−21</sup> mol/OATP molecule/min, respectively. Accordingly, the CL<inf>int</inf> value for OATP1B1∗15 was 15 % lower than that for OATP1B1∗1b, suggesting that the increased blood substrate concentrations observed in OATP1B1∗15 carriers may be due to the decreased intrinsic activity of OATP1B1∗15.

  • The effect of organic solvents on the in vitro transport activity of three OATP isoforms.

    Saito R, Akiyoshi T, Tsujii K, Takahashi R, Kataoka H, Imaoka A, Ohtani H

    Toxicology in vitro : an international journal published in association with BIBRA 107   106059 2025.03

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0887-2333

    　View Summary

    Purpose: In vitro studies of transporter activity often require the addition of organic solvents such as dimethyl sulfoxide (DMSO), methanol, and ethanol, to dissolve substrates and/or inhibitors. Although this may attenuate the transport activity, the influence of different types of organic solvents on transporter activity has not been elucidated. This study aimed to quantitatively assess the impact of organic solvents on the transport activity of organic anion transporting polypeptide (OATP) 1B1, 1A2, and 2B1. Methods: The concentration-dependent influence of DMSO, methanol, and ethanol on the uptake of [3H]estrone 3-sulfate mediated by OATP1A2, OATP2B1 or 2′,7′-dichlorofluorescein (DCF) mediated by OATP1B1 was assessed using HEK293 cells expressed the respective OATP protein and the concentration that reduced the uptake by 20 % (IC20) was calculated. Results and discussion: The uptake activities of OATPs were reduced by methanol and ethanol in a concentration-dependent manner, with IC20 values of 2.4–3.4 % and 0.51–3.8 % respectively. In contrast, DMSO did not affect the OATP2B1-mediated uptake at the maximum concentration (10 %) of DMSO whereas it exhibited concentration-dependent inhibition for OATP1B1 and 1A2 with IC20 values of approximately 3 % and 0.7 %, respectively. This study provides useful information regarding experimental conditions for evaluating OATPs activity in vitro.

  • The pharmacist role at drug store in Thailand

    Takeshi Akiyoshi

    Japanese Journal of Community Medicine and Pharmaceutical Sciences (The Japanese Association of Home Care Pharmacies)  12 ( 1 ) 41 - 47 2025

    Research paper (scientific journal), Single Work,  ISSN  2188658X

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 海外の薬局・薬学事情　タイ王国での薬局薬剤師の役割　医療格差が生む薬局薬剤師の職能域の拡大とヘルスケア提供者としての可能性

    秋好 健志

    在宅薬学 ((一社)日本在宅薬学会)  12 ( 1 ) 41 - 47 2025.04

    ISSN  2188-658X

  • Epstein-Barr-Virus 感染癌細胞における microRNA を介した癌転移機構の解明

    AKIYOSHI Takeshi

    Annual Report of YOKOYAMA Foundation for Clinical Pharmacy 25   58 - 60 2017

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), Single Work

  • P450を介した薬物相互作用に個人差をもたらす遺伝的要因の定量的解明と予測

    AKIYOSHI Takeshi

    臨床薬理の進歩 (臨床薬理研究振興財団)     128 - 129 2016

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)

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Presentations 【 Display / hide 】

  • Food-Drug Interactions via Intestinal OATPs Inhibition by Thai Fruits: -International Collaboration Study-.

    Ayae Oshikawa, Takeshi Akiyoshi, Orawan Monthakantirat, Supawadee Daodee, Yaowared Chulikhit, Riho Takahashi, Ayuko Imaoka, Hisakazu Ohtani.

    The 35th Annual Meeting of the Japanese Society of Pharmaceutical Health Care and Sciences, 

    2025.11
    , 

    Poster presentation

  • The impact of genetic variation on the pre-incubation of inhibitor of OATP1B1

    辻井一成, 平野朋子, 谷野愛実, 今岡鮎子, 秋好健志, 大谷壽一

    [Domestic presentation]  第 19 回次世代を担う若手のための医療薬科学シンポジウム, 

    2025.09
    , 

    Poster presentation

  • Determination of Intrinsic Clearance Per Transporter Molecule for Plasma Membrane Transporters.

    Takeshi Akiyoshi

    [International presentation]  Membrane Physiology Symposium 2025 (東京) , 

    2025.07
    , 

    Symposium, workshop panel (nominated)

  • Decoding OATP transport mechanisms: In Silico insghts into prodrug design and mutation induced functional changes.

    Tonduru AK, Maljaei SH, Kronenberger T, Adla S, Kataoka H, Akiyoshi T, Ohtani H, Huttunen KM, Terasaki T, Poso A.

    [International presentation]  ESMEC 2025 (Urbino) , 

    2025.06
    -
    2025.07
    , 

    Poster presentation

  • Inhibitory effect of diclofenac on the intestinal absorption of fexofenadine

    鈴木紀子, 今岡鮎子, 韓弘輝, 秋好健志, 大谷壽一

    [Domestic presentation]  第 33 回 医療薬学フォーラム2025, 

    2025.06
    , 

    Poster presentation

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

  • フェキソフェナジンとの相互作用を引き起こす柑橘果汁中阻害成分の網羅的定量解析に基づく相互作用の推定

    2024.06
    -
    2027.03

    公益財団法人一般用医薬品セルフメディケーション振興財団, 令和6年度調査・研究助成金, Research grant, Principal investigator

  • トランスポーターを介したDisease-Drug interactionsのメカニズムとその臨床的意義

    2024.04
    -
    2027.03

    文部科学省・日本学術振興会, 科学研究費助成事業 基盤研究（C）, Research grant, Principal investigator

  • Mechanisms of transporter-mediated Disease-Drug interactions and its clinical relevance

    2024.04
    -
    2027.03

    基盤研究(C), Principal investigator

  • フェキソフェナジンと解熱鎮痛剤の相互作用のリスク評価と個人間変動解析

    2022.05
    -
    2023.06

    公益財団法人一般用医薬品セルフメディケーション振興財団, 研究助成金, Research grant, Principal investigator

  • In silico analysis of DDI risk on Rare and Low-frequency variants in human CYPs and OATPs

    2021.12
    -
    2023.10

    Japan Research Foundation for Clinical Pharmacology , 2021 年度(第 46 回) 研究奨励金, Takeshi Akiyoshi, Hisakazu Ohtani, Research grant, Principal investigator

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Awards 【 Display / hide 】

  • 優秀演題発表賞

    諏訪円佳, 今岡鮎子, 秋好健志, 大谷壽一., 2023.06, 日本医療薬学会, 柑橘系果物に含有される CYPs 阻害成分の含量とその果実間差の網羅的定量解析

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • 優秀ポスター発表賞

    森田時生，佐藤稜，秋好健志, 今岡鮎子, 片山和浩, 杉本芳一, 大谷壽一. , 2018.09, 第62回日本薬学会関東支部会, ヒト小腸有機アニオン輸送ポリペプチド OATP1A2 および OATP2B1 の pH sensitive な輸送特性の解析.

    Type of Award： Award from Japanese society, conference, symposium, etc.

  • 優秀口演発表賞

    土谷聡耀, 今岡鮎子, 秋好健志, 大谷壽一, 2017.09, 第61回日本薬学会関東支部大会, イリノテカンによる消化管障害がジゴキシンの吸収に与える影響

  • 学生優秀発表賞

    ○中村 幸大,　今岡 鮎子,　秋好 健志,　大谷 壽一,　慶應大・薬., 2017.07, 第20回日本医薬品情報学会総会・学術大会, 医薬品と活性炭との相互作用の回避のための投与設計法の構築と評価

  • 優秀発表賞

    ○今岡 鮎子, 関 耕平, 秋好 健志, 大谷 壽一., 2017.06, 日本医療薬学会「第1回フレッシャーズ・カンファランス」, 薬物吸収に対する胃内 pH および食事の影響 －小動物を用いた評価－

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Courses Taught 【 Display / hide 】

  • CLINICAL PHARMACOLOGY

    2025

  • BACHELOR'S THESIS

    2025

  • ADVANCED BODY SYSTEMS AND REGULATION

    2025

  • CLINICAL PHARMACOLOGY

    2025

  • THAI PHARMACY EXPERIENCE

    2025

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