Comparative 1-Substituted Imidazole Inhibition of Cytochrome P450 Isozyme-Selective Activities in Human and Mouse Hepatic Microsomes

Abstract

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 <5 μM) by the greatest number of imidazoles, followed closely by CYP2C9. Seven imidazoles exhibited IC₅₀ values for CYP3A4/5 <0.3 μM (none for CYP2C9) and were exclusively above 300 MW. Nafimidone (MW, 236) exhibited an IC₅₀ value <0.3 μM towards CYP2D6 and CYP1A2 reactions. CYP2E1 and CYP2A6 were exclusively inhibited (IC₅₀ <5 μM) by imidazoles with MWs below ∼200. In general, mouse activities exhibited lower IC₅₀ values than in human microsomes.

Key Words :

• Cytochrome P450(CYP)-selective reactions
• 1-substituted imidazoles
• Mouse hepatic microsomes
• Human hepatic microsomes
• Inhibition