2022 Fiscal Year Final Research Report
Roles of human cytochrome P450 1A2, 2C9, and 3A4/5 enzymes in drug oxidations mediated by metabolically inactivated human hepatocytes in previously transplanted chimeric mice
| Project/Area Number |
20K07164
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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) |
清水 万紀子 昭和薬科大学, 薬学部, 准教授 (90307075)
村山 典惠 昭和薬科大学, 薬学部, 講師 (90219949)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 不活性化 / ヒト肝細胞移植マウス / フラフィリン / チエニリン酸 / アザムリン |
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| Outline of Final Research Achievements |
To investigate the respective roles of cytochromes P450 1A2, 2C9 and 3A4/5 in drug oxidation in human livers, the in vivo pharmacokinetics of coumarin, S-warfarin and diclofenac, and dexamethasone were analyzed after intravenous administrations in chimeric mice that had been transplanted with human hepatocytes. P450 1A2, 2C9, and 3A4/5 were metabolically inactivated in the humanized mice by orally pretreating them with furafylline, tienilic acid, and azamulin, respectively. After intravenous administration of probe drugs, significant differences in the concentration-time profiles of the primary metabolites coumarin 3,4-epoxide (as estimated by the levels of o-hydroxyphenylacetic acid), 7-hydroxywarfarin and 4’-hydroxydiclofenac, and 6β-hydroxydexamethasone between untreated mice and mice treated with suppressors were observed. These presumably resulted from suppressed P450 1A2, 2C9, and 3A4/5 activities in the primary oxidative metabolism in vivo.
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| Free Research Field |
薬物動態学
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| Academic Significance and Societal Importance of the Research Achievements |
特定のP450 分子種を時間依存型阻害薬（生成代謝物による酵素との共有結合による）で不活化したヒト肝ミクロゾームと対照（非処置）肝ミクロゾームを用い、各P450 分子種の薬物代謝反応へのin vitro 寄与率を簡便に検討する手法が有効であることを明らかにした。さらに本手法をヒト型モデル動物でも活用し、P450 1A2, 2C9と3A4/5酵素のin vivo薬物体内動態での寄与を調べる手法を樹立した。
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