The influence of anticancer drug on the expression of transporters

• Project/Area Number: 19K07173
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Keio University
• Principal Investigator: Akiyoshi Takeshi 慶應義塾大学, 薬学部(芝共立), 講師 (50399143)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: トランスポーター / 抗がん剤曝露 / 絶対定量プロテオミクス解析 / 消化管障害 / 標的絶対定量プロテオミクス解析 / イリノテカン曝露 / トランスポーター発現 / イリノテカン / SN-38 / 抗がん剤 / OATP / 標的絶対定量プロテオミクス / 薬物動態

Outline of Research at the Start

本研究では、ラットにおいて抗がん剤曝露時の 1) 消化管および血液脳関門における各種輸送担体の mRNA 量、蛋白質の絶対発現量および質的 (翻訳後修飾など) 変化、2) 発現変動機構に関わる microRNA や DNA のメチル化など epigenetic な変動、3) 基質薬物の消化管吸収および中枢移行性を解析する。

Outline of Final Research Achievements

The aim of this study was to evaluate the expression level of pharmacokinetics-related transporters and endogenous substance transport transporters in rats exposed to the irinotecan which caused severe intestinal damage.
The plasma membrane fraction of the tissues, such as small intestine, liver, and kidney were prepared from irinotecan-exposed rats. After trypsin digestion, the expression level of each transporter-specific peptide in the samples was measured by absolute quantitative proteomic analysis using LC-MSMS.
As a result, significant expression changes were observed in P-glycoprotein as well as in endogenous substance transport transporters. These results suggest that the exposure of irinotecan may affect the pharmacokinetics of substrate of transporter.

Academic Significance and Societal Importance of the Research Achievements

臨床上ではイリノテカンなどの抗がん剤投与時に様々なトランスポーター基質薬が併用投与される。本研究により、イリノテカン時にはP糖蛋白質の発現、特に、小腸における発現量が有意に変動したことから、ジゴキシンやダビガトランなど臨床上重要なトランスポーター基質薬の吸収量の変動が示唆れれる。さらに、本研究においては、内因性物質である胆汁酸の輸送に寄与するトランスポーター発現量の有意な変動も明らかになった。これらの変動は、最終的には様々な疾患発症のリスクを示唆しており、今後これらの臨床上の影響の程度を評価する必要がある。

Research Products

• [Journal Article] Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants. (2022)
  • Author(s): Araki N, Morita T, Akiyoshi T, Kataoka H, Yajima K, Katayama K, Imaoka A and Ohtani H
  • Journal Title: Drug Metabol Pharmacokinet Volume: 00
  • Peer Reviewed
• [Journal Article] Inhibitory effects of cranberry juice and its ingredients on intestinal OATP1A2 and OATP2B1: Identification of avicularin as a novel inhibitor (2022)
  • Author(s): Morita T, Akiyoshi T, Tsuchitani T, Kataoka H, Araki N, Yajima K, Katayama K, Imaoka A, Ohtani H
  • Journal Title: J Agric Food Chem Volume: 70 Issue: 10 Pages: 3310-3320
  • DOI: 10.1021/acs.jafc.2c00065
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory Potency and pH-dependence of OATP2B1 Inhibitors. (2021)
  • Author(s): Sato R, Akiyoshi T, Morita T, Katayama K, Yajima K, Kataoka H, Imaoka A, Ohtani H.
  • Journal Title: Drug Metabol Pharmacokinet Volume: 41 Pages: 100416-100416
  • DOI: 10.1016/j.dmpk.2021.100416
  • Peer Reviewed
• [Journal Article] The citrus fruit-derived flavanone glycoside narirutin is a novel potent inhibitor of organic anion-transporting polypeptides (2020)
  • Author(s): Morita T, Akiyoshi T, Sato R, Uekusa Y, Katayama K, Yajima K, Imaoka A, Sugimoto Y, Kiuchi F, Ohtani H.
  • Journal Title: J Agric Food Chem Volume: 68 Issue: 48 Pages: 14182-14191
  • DOI: 10.1021/acs.jafc.0c06132
  • Peer Reviewed
• [Journal Article] pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2 (2019)
  • Author(s): T. Morita, T Akiyoshi, R. Sato, K. Katayama, K. Yajima, H. Kataoka, A. Imaoka, Y. Sugimoto, H. Ohtani
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 35 Issue: 2 Pages: 220-227
  • DOI: 10.1016/j.dmpk.2019.12.002
  • NAID: 50014558590
  • Peer Reviewed / Open Access
• [Journal Article] Effects of types of food on the extent of drug-drug interaction between activated charcoal and phenobarbital in rats. (2019)
  • Author(s): Hattori T, Imaoka A, Akiyoshi T, Ohtani H.
  • Journal Title: Biopharm. Drug Dispos Volume: 40 Issue: 9 Pages: 315-324
  • DOI: 10.1002/bdd.2205
  • Peer Reviewed
• [Presentation] 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. (2023)
  • Author(s): 邉田桃子、秋好健志、矢島広大、土谷聡耀、今岡鮎子、大谷壽一.
  • Organizer: 日本薬学会第143年会
• [Presentation] 定量的標的プロテオミクスを用いた変異型 OATP1A2/OATP2B1 の輸送特性の評価. (2021)
  • Author(s): 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.
  • Organizer: 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.
• [Presentation] High and low affinity kinetics of OATP2B1 - Inhibitory potency and pH-dependency of inhibitors (2019)
  • Author(s): 佐藤 稜、秋好健志, 今岡鮎子、植草義徳、 木内文之、片山和浩、杉本芳一、大谷壽一.
  • Organizer: 日本薬物動態学会 第 34 年会
• [Presentation] Identification and characterization of a novel OATP2B1 inhibitor from citrus fruits juice (2019)
  • Author(s): 森田時生、秋好健志, 矢島広大、今岡鮎子、片山和浩、杉本芳一、大谷壽一
  • Organizer: 第 13 回 次世代を担う若手医療薬科学シンポジウム.
• [Presentation] 1)Comparative analysis of CYP2C19 enzyme kinetics among six genetic variants. (2019)
  • Author(s): Watanabe D, Shimoji M, Seki H, Akiyoshi T, Imaoka A, Murakami A, Kishimoto H, Murayama N, Yamazaki H, Nakamura K, Ohtani H
  • Organizer: Asian Association of Schools of Pharmacy Conference.
  • Int'l Joint Research