P450 interaction with farnesyl-protein transferase inhibitors - Metabolic stability, inhibitory potency, and P450 binding spectra in human liver microsomes

Methyl substitution at the 2-position of the imidazole ring greatly improved drug metabolism profiles, in human liver microsomes, of ras famesyl-protein transferase inhibitor (FTI) candidates for drug development. Methyl substitution markedly reduced the P450 inhibitory potency of non-substituted FTIs for CYP3A4 (by a factor of 12-403) and 2C9 (by a factor of 4.2-28), while it had little effect on the CYP2D6 enzyme. An immunochemical inhibition study demonstrated that CYP3A4 plays a predominant role in the metabolism of both nonsubstituted and 2-methyl-substituted imidazole-containing FTI candidates. Very strong type H binding spectra with human liver microsomes were observed for all non-substituted FTIs, while methyl substitution markedly weakened type II spectra or shifted the type of spectra from II to I. This indicated that methyl substitution on the imidazole moiety interfered with the substrate-P450 heme interaction, likely due to a steric effect caused by the methyl group. A kinetics study revealed that the methyl substitution increased V-max and K-m values to the same extent. These studies suggested that the 2-methyl substitution on the imidazole ring improved its drug metabolism profile by reducing the potential to inhibit CYP3A4-mediated metabolism without affecting intrinsic metabolic clearance (V-max/K-m). (C) 2001 Elsevier Science Inc. All rights reserved.