Structure-selective metabolome analysis of ABC xenobiotic transporters
| Project/Area Number |
18H02584
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 47060:Clinical pharmacy-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
Kato Yukio 金沢大学, 薬学系, 教授 (30251440)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
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| Keywords | メタボロミクス / 薬物動態 / バイオマーカー / トランスポーター / 薬物相互作用 / 硫酸抱合 / イソフラボン / 質量分析装置 / 実験動物 / 膜輸送体 / 医薬品開発 / 体内動態 / 生合成 / 質量分析 |
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| Outline of Final Research Achievements |
Membrane transporters are localized on plasma membranes of various cells and involved in the uptake and efflux of substrate drugs. This study focused on two drug efflux transporters, breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp), both of which are expressed in the intestine, liver, kidney, and blood-brain barrier. Many drugs are pumped out by these transporters, and therefore, administration of their inhibitor drugs may lead to change in pharmacokinetics, efficacy, and/or toxicity of their substrate drugs. We have attempted to identify compounds which exist in the body, are transported by these transporters, and whose blood concentration is changed by administration of inhibitor drugs. Comprehensive metabolomics analysis has clarified that sulfate conjugates of isoflavones and food-derived steroid-like compounds are the in vivo substrates of BCRP and P-gp, respectively. We proposed the first evidence of a surrogate marker of BCRP inhibition.
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| Academic Significance and Societal Importance of the Research Achievements |
膜輸送体は、基質薬物の体内動態を支配する一方、基質選択性が広いため、薬の飲みあわせによる薬物相互作用や遺伝子多型による薬物動態、薬の作用・副作用の変化に関与する。従って、膜輸送体に及ぼす医薬品の影響や、膜輸送体への乗りやすさを解明することは、新薬の開発と医薬品の適正使用の両方に重要である。本研究で明らかとなった、薬物排出膜輸送体の生体内基質は、今後、臨床研究等においてヒトにおける有効性を検証する必要がある。ヒトでも有効となった場合、膜輸送体を介した薬物相互作用の有無を、飲み合わせる薬を投与することなくモニターできる点で有用であり、医薬品開発の効率化や安全性の向上が期待できる。
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Report
(4 results)
Research Products
(28 results)
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[Journal Article] Higher Systemic Exposure to Unbound Active Metabolites of Regorafenib Is Associated With Short Progression-Free Survival in Colorectal Cancer Patients.2020
Author(s)
Kubota Y, Fujita KI, Takahashi T, Sunakawa Y, Ishida H, Hamada K, Ichikawa W, Tsunoda T, Shimada K, Masuo Y, Kato Y, Sasaki Y.
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Journal Title
Clin Pharmacol Ther
Volume: -
Issue: 3
Pages: 586-595
DOI
Related Report
Peer Reviewed
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