Inhibition of microsomal phenytoin metabolism by nafimidone and related imidazoles. Potency and structural considerations.

Nafimidone and other 1-imidazoles were shown to be potent inhibitors of phenytoin p-hydroxylation in rat hepatic microsomes, being very effective even at submicromolar concentrations. The inhibitory potency of these 1-imidazoles was similar to that of SKF 525-A and considerably greater than that observed for other imidazoles (4,5-diphenylimidazole, cimetidine, metronidazole), metyrapone, or other anticonvulsants. The effects of structural modification on the inhibitory activity were examined. Except at the 2-position on the imidazole, alkyl substitution increased the inhibitory potency, probably because of increased lipophilicity. Substitution at the 2-position caused marked diminution in inhibitory activity, possibly due to steric hindrance. The hydroxy analogs of nafimidone exhibited greater inhibitory activity than the corresponding keto compounds. Furthermore, pretreatment of the rats with nafimidone resulted in greater Vmax values for both low affinity and high affinity metabolic sites.