Different roles of human cytochrome P450 2C9 and 3A enzymes in diclofenac 4'- and 5-hydroxylations mediated by metabolically inactivated human hepatocytes in previously transplanted chimeric mice

To investigate the respective roles of cytochromes P450 2C9 and 3A in drug oxidation in human livers, the in vivo pharmacokinetics of S-warfarin and diclofenac were analyzed after intravenous administrations in chimeric mice that had been transplanted with human hepatocytes. P450 2C9 was metabolically inactivated in the humanized mice by orally pretreating them with tienilic acid. After intravenous administrations of S-warfarin, a significant difference in the concentration–time profiles of primary metabolite 7-hydroxywarfarin between untreated mice and mice treated with tienilic acid was observed. In contrast, there were to no apparent differences in the profiles for S-warfarin between the treated and untreated groups. The mean values of the maximum concentrations (Cmax) and the areas under the plasma concentration versus time curves (AUCinfinity) for 7-hydroxywarfarin were significantly lower (22% and 16% of the untreated values, respectively) in the treated group. This presumably resulted from suppress...