Metabolite-intermediate complexation and inhibition of microsomal CYP3A in rat liver by diltiazem.

1. The formation of metabolite intermediate (MI)-complexes between cytochrome P450 (CYP) and the alkylamine-substituted drugs diltiazem (DTZ) and desipramine (DES) and their effect on CYP activities was investigated in rat liver. 2. Dexamethasone and phenobarbitone pretreatment enhanced MI-complexation by DTZ (36% and 11% of total CYP complexed, respectively), whereas beta-naphthoflavone induction was without effect. All three treatments decreased MI-complexation produced by DES. 3. After a preincubation step in NADPH-supplemented microsomes DTZ and DES were effective inhibitors of the activities of CYPs 3A and 2C11 (testosterone 6beta- and 16alpha-hydroxylations, respectively). 4. Although MI-complexation by DTZ was more extensive in microsomes from dexamethasone-induced rats, the apparent inhibition potency of the drug toward CYP activity was unchanged. By comparison, inhibition of CYP activity by DES was less pronounced than in control liver. 5. These findings indicate that drug-mediated MI-complexation of CYPs does not necessarily potentiate the inhibitory effect on monooxygenase activity, although the duration of inhibition is longer. The extent of inhibition produced by stable drug metabolites may be similar to that from MI-complexation. but their duration of action is limited by diffusion from the active site of the enzyme.