The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat

The effect of cimetidine on rat liver microsomal drug metabolism in vitro and in vivo was studied. Cimetidine inhibits aminopyrine N-demethylation and benzo[a]pyrene hydroxylation in a noncompetitive manner with inhibition constants between 1 and 10 mM. Benzo[a]pyrene hydroxylation in liver microsomes from 3-methylcholanthrene-pretreated rats is not appreciably inhibited by cimetidine indicating some specificity in terms of different cytochrome P-450 forms. Cimetidine gives rise to a type II spectral change with a spectral dissociation constant of about 0.1 mM. The prolonged administration of cimetidine does not result in the induction of hepatic drug metabolism. Pretreatment of rats with cimetidine prolongs aminopyrine half-life and hexobarbital sleeping time. These results demonstrate that cimetidine is an in vitro inhibitor of microsomal drug metabolism in the rat and this inhibition leads to pharmacokinetic drug-drug interactions in vivo.