2018 Fiscal Year Final Research Report
Pharmacokinetics prediction of drugs in humans associated with flavin-containing monooxygenase dependent-oxygenations in livers and kidneys of animal models
| Project/Area Number |
16K08380
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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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| Research Field |
Medical pharmacy
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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) |
2016-04-01 – 2019-03-31
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| Keywords | フラビン含有酸素添加酵素 / FMO |
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| Outline of Final Research Achievements |
The flavin-containing monooxygenase (FMO) is an NADPH-dependent enzyme that catalyzes the oxygenation of a wide variety of nitrogen- and sulfur-containing medicines and xenobiotic substances. Human FMO3 and FMO1 are considered prominent functional forms expressed in adult livers and kidney, respectively. FMO dependent oxygenation activities in humanized-liver mice, marmoset, and monkey were determined. The oxidation rates of FMO substrate in mouse kidney may need to be taken into consideration when directly scaling up without consideration of an interspecies factor between in vitro hepatic clearances and in vivo clearances of FMO probe drugs in humanized-liver mice. Expression of FMO1 and FMO3 mRNA were determined in the marmoset liver and kidney. Monkey FMO1 was expressed and functional in kidneys, similar to human FMO1. These results suggest that investigation of drug-drug or drug-food interactions associated with FMO enzymes could be evaluated in non human primate models.
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| Free Research Field |
薬物代謝学、薬物動態学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、肝のみならず腎の酸素添加酵素活性を考慮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各分子種の触媒活性および薬物相互作用の情報は少なく、FMOの関与する薬物の体内動態の詳細を明らかにすることは、FMO が代謝を触媒する医薬品の開発を進める上で意義深いと考える。さらに、FMO3によって食品由来成分トリメチルアミンから生成するN酸化体は動脈硬化悪化が提唱されており、疾患の影響因子として基盤となることが期待できる。
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