Nafimidone, an imidazole anticonvulsant, and its metabolite as potent inhibitors of microsomal metabolism of phenytoin and carbamazepine.

The effects of nafimidone and its metabolite (reduced nafimidone) on p-hydroxylation of phenytoin were examined by using hepatic microsomes from rats pretreated with phenytoin. Both nafimidone and reduced nafimidone inhibited p-hydroxylation of phenytoin in a concentration-dependent manner and at both high and low affinity metabolic sites. Both compounds were effective inhibitors at submicromolar concentrations. The inhibitory pattern at both metabolic sites was consistent with "mixed type" inhibition. The inhibition constants, Ki, calculated for reduced nafimidone, were about 0.2 microM at both sites. Submicromolar concentrations of nafimidone and its metabolite also inhibited carbamazepine epoxidation. Thus, nafimidone and its metabolite were shown to be potent inhibitors of major biotransformation pathways of two important antiepileptic drugs.