P450 interaction with farnesyl-protein transferase inhibitors - Metabolic stability, inhibitory potency, and P450 binding spectra in human liver microsomes
M. Chiba et al., P450 interaction with farnesyl-protein transferase inhibitors - Metabolic stability, inhibitory potency, and P450 binding spectra in human liver microsomes, BIOCH PHARM, 62(6), 2001, pp. 773-776
Methyl substitution at the 2-position of the imidazole ring greatly improve
d drug metabolism profiles, in human liver microsomes, of ras famesyl-prote
in transferase inhibitor (FTI) candidates for drug development. Methyl subs
titution markedly reduced the P450 inhibitory potency of non-substituted FT
Is for CYP3A4 (by a factor of 12-403) and 2C9 (by a factor of 4.2-28), whil
e it had little effect on the CYP2D6 enzyme. An immunochemical inhibition s
tudy demonstrated that CYP3A4 plays a predominant role in the metabolism of
both nonsubstituted and 2-methyl-substituted imidazole-containing FTI cand
idates. 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 b
y 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 meta
bolism profile by reducing the potential to inhibit CYP3A4-mediated metabol
ism without affecting intrinsic metabolic clearance (V-max/K-m). (C) 2001 E
lsevier Science Inc. All rights reserved.