Evaluation for pharmacokinetics of chemicals mediated by flavin-containing monooxygenases using humanized animal models
| Project/Area Number |
19K07205
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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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 | Showa Pharmaceutical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
山崎 浩史 昭和薬科大学, 薬学部, 教授 (30191274)
村山 典惠 昭和薬科大学, 薬学部, 講師 (90219949)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | フラビン含有酸素添加酵素 / FMO |
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| Outline of Research at the Start |
フラビン含有酸素添加酵素による代謝を受ける医薬品および化学物質を投与し、各種実験動物における血中化学物質濃度およびその代謝物濃度を測定し、その実測値をコンピューター上で再現する生理学的薬物動態モデルの構築を行う。さらに、薬物代謝酵素活性変動要因の検討を行う。フラビン含有酸素添加酵素が介する医薬品と化学物質の体内動態をヒト型モデル動物を用いて評価し、酵素基質や阻害薬共存下のヒト体内薬物動態予測へ応用することを目指す。
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| Outline of Final Research Achievements |
The flavin-containing monooxygenase (FMO) catalyzes the oxygenation of medicines and dietary-derived compounds. However, little information regarding apparent drug interactions has been reported so far for FMO3. Therefore, the purpose of the present study was to investigate the interactions of FMO substrates using humanized-liver mice. In humanized-liver mice, itopride was extensively oxygenated to its N-oxide detected in plasma, whereas control mice were poor metabolizers for itopride. The plasma concentrations of itopride N-oxide after oral administration of itopride with intravenous trimethylamine were significantly suppressed by co-administered trimethylamine only at early phase. Pharmacokinetics modeling suggested that the higher dose of trimethylamine modified the in vivo hepatic intrinsic clearance of itopride. These results suggest that trimethylamine lead to drug interactions for FMO substrate at immediately after administration in vivo, but the potential might be limited.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、ヒト型モデル動物を用いて生体内でFMO基質の体内動態に影響する因子を評価する点に学術的意義がある。医薬品開発で用いられている実験動物の肝および腎のFMO各分子種の情報は少なく、FMOが消失に関与する薬物の体内動態の詳細を明らかにすることは、新たな医薬品開発におけるFMOの代謝を考察する上で意義深いと考える。食品由来成分との相互作用は日常での医薬品の適正使用に対して基盤となる情報として期待できる。
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Report
(4 results)
Research Products
(18 results)
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[Journal Article] Genetic variants of flavin-containing monooxygenase 3 (FMO3) derived from Japanese subjects with the trimethylaminuria phenotype and whole-genome sequence data from a large Japanese database.2019
Author(s)
Shimizu, M., Yoda, H., Nakakuki, K., Saso, A., Saito, I., Hishinuma, E., Saito, S., Hiratsuka, M., Yamazaki, H.
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Journal Title
Drug Metab. Pharmacokinet.
Volume: 34
Issue: 5
Pages: 334-339
DOI
NAID
Related Report
Peer Reviewed
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