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
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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 】

  • 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

    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.

  • Kinetics of the Inhibition of CYP3A4 and CYP2C19 Activity by Jabara Juice and Identification of the Responsible Inhibitory Components.

    Koinuma K, Noto K, Morita T, Uekusa Y, Kikuchi H, Shimoji M, Seki H, Yamazaki H, Guengerich FP, Nakamura K, Yamamoto K, Imaoka A, Akiyoshi T, Ohtani H

    Journal of pharmaceutical sciences 114 ( 2 ) 849 - 856 2024.10

    ISSN  0022-3549

    　View Summary

    Some citrus fruits are known to cause clinically significant drug interactions by inhibiting intestinal cytochrome P450 (CYP) enzymes. This in vitro study aimed to investigate the kinetics of the inhibition of CYP3A4 and CYP2C19 by the juice of jabara, a Japanese citrus fruit that does not contain furanocoumarins such as 6′,7′-dihydroxybergamottin, and to identify the inhibitory compound(s). CYP3A4 and CYP2C19 activity levels were determined in vitro using recombinant CYP preparations and their respective substrates. The ethyl acetate extract (EAE) of jabara juice was separated to isolate and identify the compound(s) that inhibited CYP3A4. Then, the time-dependent kinetics of the inhibition of CYP3A4 and CYP2C19 by the EAE and its inhibitory compound(s) were analyzed. The EAE of jabara juice was found to inhibit CYP3A4 in a time-dependent manner. Two flavonoids, 3,3′,4′,5,6,7,8-heptamethoxyflavone (HpMF) and 3,3′,4′,5,6,7-hexamethoxyflavone (HxMF), were identified as the responsible compounds. HpMF and HxMF inhibited CYP3A4 activity in a concentration- and time-dependent manner, with inhibition constants (KI) of 10.0 and 7.90 µM and maximal inactivation rate constants (kinact,max) of 0.00856 and 0.0134 min−1, respectively. The EAE did not inhibit CYP2C19, even when preincubation was employed. These findings imply that jabara juice may cause food-drug interactions via time-dependent inhibition of intestinal CYP3A4.

  • 低頻度バリアント保有者における薬物相互作用リスクの予測精度を改善するためのin vitro & in silico研究

    秋好 健志

    臨床薬理の進歩 ((公財)臨床薬理研究振興財団)   ( 45 ) 142 - 151 2024.06

    ISSN  0914-4366

    　View Summary

    CYP3A4に対する代表的なMBI阻害剤であるエリスロマイシンおよびクラリスロマイシンのMBIキネティクスに対する遺伝子変異の影響が、結合部位の異なる基質を用いて評価した際に異なって観測されるのか、その違いは低頻度バリアントにおける薬物相互作用にどの程度影響を及ぼすのかをin vitro試験により検討した。結果、エリスロマイシンとクラリスロマイシンはいずれも各CYP3A4 variantsのミダゾラム1-水酸化を濃度依存的およびpreincubation時間依存的に阻害し、そのMBIパラメータはvariants間で異なり、変動のパターンはテストステロンを基質とした場合と類似していた。これらのことから、MBI阻害剤の阻害キネティクスは遺伝子変異の影響を受けるが、その影響は結合部位が異なる基質間で類似している可能性が示唆された。

  • The Effects of N-Glycosylation on the Expression and Transport Activity of OATP1A2 and OATP2B1.

    Kataoka H, Akiyoshi T, Uchida Y, Imaoka A, Terasaki T, Ohtani H

    Journal of pharmaceutical sciences (Journal of Pharmaceutical Sciences)  113 ( 5 ) 1376 - 1384 2024.03

    ISSN  0022-3549

    　View Summary

    Organic anion transporting polypeptide (OATP)1A2 and OATP2B1 have potential N-glycosylation sites, but their influence remains unclear. This study aimed to identify the N-glycosylation sites of OATP1A2/2B1 and investigate their impact on the expression and function of OATP1A2/2B1. Human embryonic kidney cells expressing OATP1A2 or OATP2B1 (HEK293-OATP1A2/2B1) were exposed to tunicamycin, an N-glycosylation inhibitor, and a plasma membrane fraction (PMF) Western blot assay and an estrone 3-sulfate (E3S) uptake study were conducted. HEK293-OATP1A2/OATP2B1 cell lines with mutation(s) at potential N-glycosylation sites were established, and the Western blotting and uptake study were repeated. Tunicamycin reduced the PMF levels and E3S uptake of OATP1A2/OATP2B1. The Asn124Gln, Asn135Gln, and Asn492Gln mutations in OATP1A2 and Asn176Gln and Asn538Gln mutations in OATP2B1 reduced the molecular weights of the OATP molecules and their PMF levels. The PMF levels of OATP1A2 Asn124/135Gln, OATP1A2 Asn124/135/492Gln, and OATP2B1 Asn176/538Gln were further reduced. The maximum transport velocities of OATP1A2 Asn124Gln, OATP1A2 Asn135Gln, and OATP2B1 Asn176/538Gln were markedly reduced to 10 %, 4 %, and 10 % of the wild-type level, respectively. In conclusion, the N-glycans at Asn124 and Asn135 of OATP1A2 and those at Asn176 and Asn538 of OATP2B1 are essential for the plasma membrane expression of these molecules and also affect their transport function.

  • 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.

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 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 】

  • 柑橘果汁と医薬品の相互作用～その多様なメカニズムと個人差～

    秋好健志

    第34回医療薬学会, 

    2024.11
    , 

    Symposium, workshop panel (nominated)

  • 薬物消化管吸収を担う薬物輸送担体の機能変動

    秋好健志

    第34回医療薬学会, 

    2024.11
    , 

    Symposium, workshop panel (nominated)

  • How the irinotecan exposure affects the transport activity of P-glycoprotein in the rat small intestine

    Sekiba H, Imaoka A, Nabeta M, Tsuchitani T, Nishimura T, Akiyoshi T, Ohtani H.

    Asia Pacific Oncology Pharmacy Congress 2024, 

    2024.10
    , 

    Poster presentation

  • 消化管上皮細胞単層膜の薬物透過性に及ぼす ultrafine bubble の影響

    1) 阿部省吾, 古原里奈, 下坂紗貴子, 今岡鮎子, 田中英之, 田中俊也, 藤岡沙都子, 秋好健志, 寺坂宏一, 大谷壽一

    第68回日本薬学会関東支部大会 (新潟) , 

    2024.09
    , 

    Poster presentation, 日本薬学会関東支部会

  • トランスポーター１分子あたりの輸送活性を測る

    1) 秋好健志

    第18回トランスポーター研究会 (静岡) , 

    2024.06
    , 

    Symposium, workshop panel (nominated)

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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 】

  • SEMINAR:(CLINICAL PHARMACY)

    2025

  • RESEARCH FOR BACHELOR'S THESIS 1

    2025

  • PRIOR LEARNING FOR CLINICAL PRACTICE 4

    2025

  • PRIOR LEARNING FOR CLINICAL PRACTICE 2

    2025

  • PRE-CLINICAL TRAINING FOR HOSPITAL & COMMUNITY PHARMACY

    2025

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