Inhibition and induction of hepatic drug metabolism in rats and mice by nafimidone and its major metabolite nafimidone alcohol

Nafimidone, a candidate anticonvulsant agent, and its metabolite (nafimidone alcohol) demonstrated potent inhibition of hepatic drug metabolism in male rats. Inhibition occurred both in vivo following acute administration as a prolongation of hexobarbital sleeping time and as an elevation of plasma hexobarbital levels, and in vitro following addition to hepatic microsomes as a disruption of ethyl-morphine N-demethylation and aniline p-hydroxylation. Inhibition of ethylmorphine N-demethylation was of a mixed type, whereas aniline p-hydroxylation was inhibited in a noncompetitive manner; the micromolar K(1) values obtained for both enzymes were severalfold lower than those obtained for imidazole. Nafimidone alcohol produced a type II difference spectrum when added to rat hepatic microsomes. The K(s) value was 2.1 µM. Chronic administration of nafimidone alcohol caused induction of hepatic drug metabolism typified by shortening of pentobarbital sleeping time in vivo in male mice and a doubling of hepatic microsomal cytochrome P-450 content in male rats. In rats, these changes were associated with a 30-fold elevation in the V(max) for microsomal ethoxyresorufin O-deethylase and a moderate increase in the V(max) for microsomal ethylmorphine N-demethylase, but no change in either the rate of aniline p-hydroxylation, 4-hydroxybiphenyl- or 4-methylumbelliferone UDP-glucuronosyltransferase, or the activity of the flavoprotein reductase component. These data suggest induction of a predominating cytochrome P-448-type of Phase 1 drug-metabolizing activity by nafimidone alcohol.