Akiyoshi, Takeshi



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


Assistant Professor/Senior Assistant Professor

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Profile Summary 【 Display / hide

Academic Degrees 【 Display / hide

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

Licenses and Qualifications 【 Display / hide

  • 薬剤師, 2001.05


Research Areas 【 Display / hide

  • Life Science / Clinical pharmacy (Clinical pharmacokinetics)

Research Keywords 【 Display / hide

  • Genetic variation・Epigeneitcs

Research Themes 【 Display / hide

  • Pharmacokinetics Pharmacodynamics/Drug interaction, Polymorphism/Epigenetics, 


     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.


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

Papers 【 Display / hide

  • 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

    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.

  • Mechanistic bottom-up estimation of passive drug absorption from the gastrointestinal tract: Comparison among primary cultured human intestinal cells, Caco-2 cells, artificial membrane, and animal scale-up.

    Tsuchitani T, Akiyoshi T, Imaoka A, Ohtani H

    International journal of clinical pharmacology and therapeutics (International journal of clinical pharmacology and therapeutics)  60 ( 5 ) 217 - 224 2022.03

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0946-1965

     View Summary

    OBJECTIVE: The fraction of drug absorbed (Fa) from the intestine is an important parameter to characterize the pharmacokinetics of a drug. We aimed to search for an experimental system that provides the best parameters for estimating the effective permeability (Peff) used for the bottom-up prediction of Fa. MATERIALS AND METHODS: The absorption kinetics of 12 passively absorbed drugs were simulated by a compartment absorption transit (CAT) model using absorption parameters from four different experimental systems: human intestinal epithelial cell (HIEC) monolayer, Caco-2 monolayer, parallel artificial membrane permeability assay (PAMPA), and in situ rat intestinal perfusion. All absorption parameters were obtained from the literature. The in vitro apparent permeability coefficient (Papp) and rat in situ Peff were converted to human Peff using a bottom-up approach for each region, based on the morphological features of the human intestine. The simulated Fa values were compared to the respective observed values. Furthermore, plasma concentration profiles of the drugs were simulated by convolution using the time-course of the absorption rate simulated using the Peff values calculated from the HIEC Papp. RESULTS: The Fa values were best predicted by using the Peff values calculated from HEIC, within a 1.3-fold range of observed Fa in 11 out of 12 drugs. The simulated Cmax values of pharmacokinetic simulation using HIEC Papp fell within a 1.5-fold range of observed values for all the drugs examined. CONCLUSION: The HIEC monolayer was identified as the most suitable permeation parameter for estimating Fa and Cmax using a morphological feature-based bottom-up approach.

  • Inhibitory effects of cranberry juice and its components on intestinal OATP1A2 and OATP2B1: Identification of avicularin as a novel inhibitor

    Tokio Morita, Takeshi Akiyoshi, Toshiaki Tsuchitani, Hiroki Kataoka, Naoya Araki, Kodai Yajima, Kazuhiro Katayama, Ayuko Imaoka, Hisakazu Ohtani

    J Agric Food Chem (Journal of Agricultural and Food Chemistry)  In press ( 10 ) 3310 - 3320 2022.02

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8561

     View Summary

    Organic anion-transporting polypeptide (OATP) 1A2 and OATP2B1 mediate the intestinal absorption of drugs. This study aimed to identify fruit juices or fruit juice components that inhibit OATPs and assess the risk of associated food-drug interactions. Inhibitory potency was assessed by examining the uptake of [3H]estrone 3-sulfate and [3H]fexofenadine into HEK293 cells expressing OATP1A2 or OATP2B1. In vivo experiments were conducted using mice to evaluate the effects of cranberry juice on the pharmacokinetics of orally administered fexofenadine. Of eight examined fruit juices, cranberry juice inhibited the functions of both OATPs most potently. Avicularin, a component of cranberry juice, was identified as a novel OATP inhibitor. It exhibited IC50 values of 9.0 and 37 μM for the inhibition of estrone 3-sulfate uptake mediated by OATP1A2 and OATP2B1, respectively. A pharmacokinetic experiment revealed that fexofenadine exposure was significantly reduced (by 50%) by cranberry juice. Cranberry juice may cause drug interactions with OATP substrates.

  • Evaluation of hepatic CYP3A enzyme activity using endogenous markers in lung cancer patients treated with cisplatin, dexamethasone, and aprepitant.

    Hibino H, Sakiyama N, Makino Y, Makihara-Ando R, Horinouti H, Fujiwara Y, Kanda S, Goto Y, Yoshida T, Okuma Y, Shinno Y, Murakami S, Shirasawa M, Watabe J, Jo H, Tamura N, Tanaka T, Arakawa S, Takamizawa S, Hashimoto H, Akiyoshi T, Imaoka A, Ohe Y, Yamaguchi M, Ohtani H.

    Eur J Clin Pharmacol. (European Journal of Clinical Pharmacology)  Accepted ( 4 ) 613 - 621 2022.01

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  0031-6970

     View Summary

    Purpose: Aprepitant is used with dexamethasone and 5-HT3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant. Methods: Urinary 11β-hydroxytestosterone (11β-OHT)/testosterone concentration ratio and plasma 4β-hydroxycholesterol (4β-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers. Results: The urinary 11β-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4β-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4β-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy. Conclusion: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.

  • Analysis of inhibition kinetics of three beverage ingredients, bergamottin, dihydroxybergamottin and resveratrol, on CYP2C9 activity.

    Akiyoshi T, Uchiyama M, Inada R, Imaoka A, Ohtani H.

    Drug metabolism and pharmacokinetics (Drug Metabolism and Pharmacokinetics)  In press   100429 2021.10

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

     View Summary

    Some grapefruit juice (GFJ) ingredients and resveratrol, a fruit-derived phytoalexin, are known to inhibit cytochrome P450 (CYP) 2C9. However, their inhibition modes and detailed inhibition kinetics remain undetermined. This study aimed to investigate the inhibitory effects of two GFJ ingredients, bergamottin (BG) and dihydroxybergamottin (DHB), and resveratrol on CYP2C9 activity in vitro. DHB inhibited CYP2C9 activity, as assessed by warfarin 7-hydroxylation, in a preincubation time-dependent manner (i.e., mechanism-based inhibition; MBI), in the same manner as CYP2C19 and CYP3A4. The maximal inactivation rate (kinact,max) was 0.0638 min−1 and 0.12- and 0.26-fold of that for CYP2C19 and CYP3A4, respectively. BG showed both MBI and time-independent competitive inhibition. Resveratrol showed non-competitive inhibition with an inhibition constant (Ki) of 3.64 μM. Unlike the inhibition of CYP2C19 and CYP3A4, resveratrol did not induce MBI. These findings are important for estimating the risk of drug interactions between CYP2C9 substrates and some beverages. (146 words)

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

Reviews, Commentaries, etc. 【 Display / hide

  • 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

  • マグネシウムの消化管吸収に対するシプロフロキサシンの影響

    鈴木 玲奈, 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)  142年会   27PO5 - am2 2022.03

    ISSN  0918-9823

  • 代謝酵素の変異は薬物相互作用に個人差をもたらすか? in silicoでのアプローチ

    酒井 悠輔, 宮崎 乃絵, 秋好 健志, 今岡 鮎子, 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)  23回   81 - 81 2021.06

  • 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

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Presentations 【 Display / hide

  • The quantitative targeted absolute proteomics analysis of OATP1A2/2B1 meditated transport

    片岡寛樹, 秋好健志, 森田時生, 矢島広大, 今岡鮎子, 片山和浩, 内田康雄, 寺崎哲也, 大谷壽一.

    医療薬学フォーラム2021/第29回クリニカルファーマシーシンポジウム (沖縄) , 


    Poster presentation, 日本薬学会

  • The effect of pH condition on metabolic profiles of CYP2C19 variants

    池田理紗, 秋好健志, 関 博行, 今岡鮎子, 山崎浩史, 下地みゆき, 中村克徳, 大谷壽一.

    医療薬学フォーラム2021/第29回クリニカルファーマシーシンポジウム (沖縄) , 


    Poster presentation, 日本薬学会

  • Time-dependent inhibition profiles of fruit-components on CYP2C19genetic variants mediated metabolism

    2) 関博行, 秋好健志, 下地みゆき, 今岡鮎子, 山崎浩史, 中村克徳, 大谷壽一.

    医療薬学フォーラム2021/第29回クリニカルファーマシーシンポジウム. (沖縄) , 


    Poster presentation, 日本薬学会

  • The influence of *23 allele on the CYP2C19 metabolic kinetics.

    渡辺大智, 栗田祐作, 秋好健志, 関博行, 今岡鮎子, 村山典恵, 山崎浩史, 下地みゆき, 中村克徳, 大谷壽一.

    医療薬学フォーラム2021/第29回クリニカルファーマシーシンポジウム (沖縄) , 


    Poster presentation, 日本薬学会

  • The evaluation of fexofenadine transport kinetics mediated by OATP1A2 genetic variants

    韓 弘燁, 森田時生, 秋好健志, 片岡寛樹, 今岡鮎子, 片山和浩, 大谷壽一.

    医療薬学フォーラム2021/第29回クリニカルファーマシーシンポジウム (沖縄) , 


    Poster presentation, 日本薬学会

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

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


    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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    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


    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~


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

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


    薬学研究奨励財団, 薬学研究奨励財団 研究助成金, Takeshi Akiyoshi, Research grant, Principal investigator

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Awards 【 Display / hide

  • 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-

  • 優秀発表賞

    ○四元 敬一, 今岡 鮎子, 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」, 5-FU誘発性消化管障害時のジゴキシンの吸収変動

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Courses Taught 【 Display / hide











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