2022 Fiscal Year Final Research Report
Development of a composite humanized liver chimeric mouse that contributes to pharmacokinetic studies and its application to drug discovery research
Project/Area Number |
19H03150
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 42040:Laboratory animal science-related
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Research Institution | Central Institute for Experimental Animals |
Principal Investigator |
Suemizu Hiroshi 公益財団法人実験動物中央研究所, 研究部門, 部門長 (40332209)
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Project Period (FY) |
2019-04-01 – 2023-03-31
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Keywords | ヒト肝キメラマウス / 薬物動態 / ヒト肝細胞 / 薬物体内分布 / タンパク結合 |
Outline of Final Research Achievements |
In this study, we aimed to develop a human ADME model with reduced effects of mouse plasma proteins by generating humanized liver chimeric mice deficient in two major plasma proteins, Albumin (Alb) and Alpha-1-acid Glycoprotein 1 (Agp1). The expression of human drug metabolism-related genes in the liver of Alb/Agp1 double KO humanized liver chimeric mice was similar to that of traditional humanized liver chimeric mice, suggesting that the effect of these plasma protein deficiencies was limited. In this model, there was a large discrepancy between the predicted and measured drug metabolism clearance value for Diazepam in humans. However, the predicted value of drug metabolism clearance in humans for Ketoprofen and UCN-01 provided by Alb/Agp1 double KO humanized liver chimeric mice was similar to the measured value in humans.
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Free Research Field |
実験動物学
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Academic Significance and Societal Importance of the Research Achievements |
薬物の代謝・動態には実験動物とヒトとの間に大きな種差があり、モデル動物のヒト型化が学術上の課題である。ヒト肝細胞保有マウスの開発により肝臓における薬物代謝の種差を定性的、定量的に評価することが可能になったが、体内分布を左右する血漿タンパクの組成は依然としてマウス型であった。本研究では薬物と結合する主要な2つの血漿タンパク(アルブミンとα1酸性糖タンパク質)を欠損したヒト肝細胞保有マウスを開発した。ヒト型肝薬物代謝に加え、体内分布もヒト型化されたADMEヒト型モデルは、より精緻なヒト薬物代謝・動態予測モデルになることが期待される。
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