Akiyoshi, Takeshi

写真a

Affiliation

School of Medicine, Department of Clinical Pharmacy Department of Clinical pharmacokinetics （Shinanomachi）

Position

Assistant Professor/Senior Assistant Professor

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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 】

  • 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.

  • 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 FP, Nakamura K, Yamamoto K, Akiyoshi T, Ohtani H

    Xenobiotica; the fate of foreign compounds in biological systems （Xenobiotica)  53 （ 5 ） 1 - 9 2023.08

    ISSN  0049-8254

    　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.

  • 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 & drug disposition （Biopharmaceutics and Drug Disposition)  44 （ 5 ） 372 - 379 2023.07

    ISSN  0142-2782

    　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.

  • 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 2022.08

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

    　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.

  • Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants.

    Araki N, Morita T, Akiyoshi T, Kataoka H, Yajima K, Katayama K, Imaoka A, Ohtani H

    Drug metabolism and pharmacokinetics （Drug Metabolism and Pharmacokinetics)  46   100464 2022.05

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

    　View Summary

    Non-synonymous genetic variants of organic anion-transporting polypeptide (OATP) 1A2 with altered transport activity have been identified. Naringin and narirutin, which are found in grapefruit, and their aglycon naringenin inhibit OATP1A2. However, their inhibitory effects on OATP1A2 variants have not been investigated, nor has the influence of their molecular structure, such as the number of sugar moieties, on their inhibitory potency. This study aimed to investigate the inhibitory effects of naringenin, its monosaccharide glycoside prunin, and its disaccharide glycosides naringin and narirutin on fexofenadine (FEX) uptake by OATP1A2 variants (Ile13Thr, Asn128Tyr, Ala187Thr, and Thr668Ser). Naringin, narirutin, and prunin inhibited FEX (0.3 μM) uptake by all of the examined OATP1A2 variants in a concentration-dependent manner. Compared with those for the wild type, the inhibition constants (Ki) of naringin, narirutin, and prunin for the Ala187Thr variant were significantly increased by 3.36-fold, 7.55-fold, and 10.6-fold, respectively. Naringenin inhibited all of the OATP1A2 variants, except Ala187Thr, concentration-dependently. The order of inhibitory potency was as follows for all variants: aglycone > monosaccharide glycoside > disaccharide glycosides. These results suggest that the Ala187Thr variant is less vulnerable to inhibition by naringenin and its glycosides. Moreover, greater glycosylation of naringenin reduces its inhibitory potency against OATP1A2.

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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 】

  • ジャバラ果汁と Fexofenadine との薬物相互作用に関する in vivo ＆ in vitro 解析

    韓弘燁, 秋好健志, 森田時生, 土谷聡耀, 邉田桃子, 矢島広大, 今岡鮎子, 大谷壽一.

    第 6 回フレッシャーズカンファランス (京都) , 

    2023.06
    , 

    Oral presentation (general), 一般社団法人日本医療薬学会

  • 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

    諏訪円佳, 今岡鮎子, 秋好健志, 大谷壽一.

    第 6 回フレッシャーズカンファランス (京都) , 

    2023.06
    , 

    Poster presentation, 一般社団法人日本医療薬学会

  • ラット肝・腎・小腸組織におけるトランスポーター発現量解析とイリノテカン曝露の影響.

    邉田桃子, 土谷聡耀, 矢島広大, 秋好健志, 今岡鮎子, 大谷壽一.

    日本薬学会第143年会 (札幌) , 

    2023.03
    , 

    Oral presentation (general), 日本薬学会

  • Ultrafine bubble が Caco-2 細胞単層膜における薬物の受動拡散に及ぼす影響.

    古原里奈, 下坂沙貴子, 今岡鮎子, 田中英行, 藤岡沙都子, 秋好健志, 寺坂宏一, 大谷壽一.

    日本薬学会第143年会 (札幌) , 

    2023.03
    , 

    Poster presentation, 日本薬学会

  • ラットにおける axitinib の消化管吸収に対する curcumin の影響.

    安永真帆, 大橋佳奈, 土谷聡耀, 辻井一成, 今岡鮎子, 秋好健志, 大谷壽一.

    日本薬学会第143年会 (札幌) , 

    2023.03
    , 

    Poster presentation, 日本薬学会

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

  • 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

  • -

    2020.06
    -
    2021.03

    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2年度調査・研究助成金, Research grant, Principal investigator

  • 標的絶対定量プロテオーム解析を用いた抗がん剤曝露下での薬物輸送担体発現変動解明

    2020.04
    -
    2021.03

    中冨健康科学振興財団, 第３２回中冨健康科学振興財団 「研究助成金」, Research grant, Principal investigator

  • 抗がん剤による薬物トランスポーターの発現変動～メカニズムと薬物体内動態への影響～

    2019.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), 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 】

  • THAI PHARMACY EXPERIENCE

    2023

  • 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

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