Drug metabolism by rat and human hepatic microsomes in response to interaction with H₂-receptor antagonists

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(K_s = 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.