Comparative 1-substituted imidazole inhibition of cytochrome P450 isozyme-selective activities in human and mouse hepatic microsomes

Inhibition of cytochrome P450(CYP)-selective reactions in a single human and a single mouse hepatic microsome preparation by fourteen 1-substituted imidazoles provides a simultaneous ranking of reaction susceptibility to a specific imidazole and the relative inhibitory potency of the imidazoles for a given reaction. CYP3A4/5 activity was inhibited (IC50 < 51 mu M) by the greatest it umber of imidazoles, followed closely by CYP2C9. Seven imidazoles exhibited IC50 values for CYP3A4/5 < 0.3 mu M (none for CYP2C9) and were exclusively above 300 MW. Nafimidone (MW, 236) exhibited an IC50 value < 0.3 mu M towards CYP2D6 and CYP1A2 reactions. CYP2E1 and CYP2A6 were exclusively inhibited (IC50 < 5 mu M) by imidazoles with MWs below similar to 200. In general, mouse activities exhibited lower IC50 values than in human microsomes.