PT - JOURNAL ARTICLE AU - Tae Inoue AU - Kayoko Nitta AU - Kazumi Sugihara AU - Toru Horie AU - Shigeyuki Kitamura AU - Shigeru Ohta TI - CYP2C9-Catalyzed Metabolism of <em>S</em>-Warfarin to 7-Hydroxywarfarin in Vivo and in Vitro in Chimeric Mice with Humanized Liver AID - 10.1124/dmd.108.022830 DP - 2008 Dec 01 TA - Drug Metabolism and Disposition PG - 2429--2433 VI - 36 IP - 12 4099 - http://dmd.aspetjournals.org/content/36/12/2429.short 4100 - http://dmd.aspetjournals.org/content/36/12/2429.full SO - Drug Metab Dispos2008 Dec 01; 36 AB - Chimeric mice having humanized livers were constructed by transplantation of human hepatocytes. In this study, we investigated whether these mice have a capacity for drug metabolism similar to that of humans by examining hydroxylation of S-warfarin, which is predominantly metabolized to S-7-hydroxywarfarin, catalyzed by CYP2C9, in humans but not mice. The 7-hydroxylating activity of chimeric mouse liver microsomes toward S-warfarin was approximately 10-fold higher than that of control (urokinase-type plasminogen activator-transgenic severe combined immunodeficient) mice. The 7-hydroxylase activity of chimeric mouse liver microsomes was markedly inhibited by sulfaphenazole, as was that of human liver microsomes, whereas the activity of control mice was unaffected. The CYP2C isoform in chimeric mouse liver was also confirmed to be the human isoform, CYP2C9, by immunoblot analysis. In the present in vivo study, the level of S-7-hydroxywarfarin in plasma of chimeric mice was approximately 7-fold higher than that in control mice, in agreement with the in vitro data. Thus, the CYP2C isoform in chimeric mice functions in vivo and in vitro as a human isoform, CYP2C9. These results suggest that chimeric mice with humanized liver could be useful for predicting drug metabolism in humans, at least regarding CYP2C9-dependent metabolism. The American Society for Pharmacology and Experimental Therapeutics