Cimetidine has been reported to decrease plasma clearance of drugs in humans and animals. This reduction in hepatic drug metabolism could be due to cimetidine's intrinsic H2-receptor blocking activity. Alternatively, the imidazole ring structure of cimetidine could explain these observations because imidazole derivatives have been reported to be potent inhibitors of hepatic microsomal drug metabolism. Rat and human hepatic microsomal drug metabolism in the presence of cimetidine and ranitidine, a nonimidazole H2-receptor antagonist, have been studied. High binding affinity of cimetidine for cytochrome P450(Ks = 31 μM) was seen, while no evidence for ranitidine binding to cytochrome P450 was observed. Cimetidine inhibited meperidine and pentobarbital metabolism by both rat and human hepatic microsomes while ranitidine did not affect these two cytochrome P450-mediated biotransformation reactions. Conjugation of morphine, a reaction not mediated by cytochrome P450, was unaffected by either cimetidine or ranitidine. The imidazole structure of cimetidine rather than its H2-receptor blocking activity is primarily responsible for cimetidine-induced inhibition of hepatic drug metabolism.