Comparison of imidazole- and 2-methyl imidazole-containing farnesyl-protein transferase inhibitors: interaction with and metabolism by rat hepatic cytochrome P450s.

Methylation at the 2-position of the imidazole ring of IBN (I), a 1, 5-substituted imidazole-containing compound, was carried out to minimize its inhibition of rat cytochrome P450 (CYP)3A activity. The resulting analog 2-MIBN (II) exhibited an inhibitory potency 70-fold weaker (K(i) = 25 microM) than that of I (K(i) = 0.3 microM) toward CYP3A, the major rat liver microsomal P450 isoform(s) for the metabolism of I and II by rat liver microsomes in the presence of NADPH.

Comparative in vitro metabolism of indinavir in primates--a unique stereoselective hydroxylation in monkey.

1. The in vitro metabolism of indinavir (CRIXIVAN, MK-0639, L-735,524), an HIV protease inhibitor, was evaluated using liver microsomes from cynomolgus monkey, rhesus monkey, chimpanzee and human. Indinavir exhibited marked species differences in metabolism.

Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4.

Caco-2 cells grown in the presence of 1alpha,25-di-OH vitamin D(3) (di-OH vit D(3)) were used as a model to evaluate the effects of P-glycoprotein (Pgp) efflux on CYP3A4-mediated metabolism of indinavir during intestinal absorption. Caco-2 cells grown under these conditions demonstrated significant CYP3A4 activity and maintained Pgp-mediated directional transport of indinavir. Metabolism of indinavir in the di-OH vit D(3)-treated cells correlated with the level of CYP3A activity and generated metabolites consistent with CYP3A4-mediated metabolism.

Effect of dexamethasone on the intestinal first-pass metabolism of indinavir in rats: evidence of cytochrome P-450 3A [correction of P-450 A] and p-glycoprotein induction .

Indinavir, a potent and specific inhibitor of HIV protease, is a known substrate of cytochrome P-450 (CYP) 3A and p-glycoprotein. The purpose of this study is to investigate and compare the inducing effect of dexamethasone (DEX) on CYP3A and p-glycoprotein in the hepatic and intestinal first-pass metabolism of indinavir in rats. Pretreatment of rats with DEX had little effect on the pharmacokinetics (Cl and T(1/2)) after i.