Drug interactions through binding to cytochrome p 450: the experience with h2-receptor blocking agents.

H2-receptor blocking agents, such as cimetidine, ranitidine or oxmetidine, are consumed in large amounts often together with a variety of other drugs. There is increasing evidence that cimetidine interferes with the hepatic elimination of several drugs, thereby aggravating the effects of the comedication. Microsomal studies in vitro revealed that cimetidine binds in therapeutic concentrations to cytochrome P450, which may represent the primary mechanism for its ability to inhibit drug metabolism and thereby interact with other drugs. The structurally different ranitidine (replacement of the imidazole in cimetidine by a furan ring) is about five times as potent as a H2-receptor blocker and displays low affinity for binding sites on cytochrome P 450. Therefore, therapeutic doses of ranitidine do not impair the metabolism of other drugs. Preliminary data with oxmetidine suggest that it too does not interfere at the level of hepatic elimination. Thus, it is concluded that new therapeutic agents should be tested for their ability to bind to cytochrome P 450 to determine possible risks of drug interactions.