Famotidine: A Notable Lack of Drug Interactions

Abstract

Cimetidine, an H₂-receptor antagonist, has been shown to inhibit the oxidative metabolism of several drugs by interacting with the hepatic cytochrome P450 system, which is involved in phase-I oxidative drug metabolism. Ranitidine, another H₂-receptor antagonist, has been shown to have an extremely low level of interaction with the cytochrome P450 system. The potential of famotidine, a new H₂-receptor antagonist with a guanylthiazole ring structure, to interact with the cytochrome P450 system has been extensively evaluated. Many of the studies used cimetidine and/or ranitidine as active controls. In vitro studies investigated the potential effects of famotidine coadministration on aminopyrine and diazepam demethylase activity, disturbances of P450 spectra, and effects on the metabolism of specific substrates such as deethylation of 7-ethoxycoumarin and demethylation of benzphetamine. Famotidine and ranitidine showed negligible interaction with the cytochrome P450 reactions studied, in contrast to the rather marked interaction demonstrated with cimetidine. Several in vivo animal studies investigated the effect of famotidine on hexobarbital sleeping time; plasma concentrations of diazepam, warfarin, and propranolol; antipyrine elimination kinetics; and warfarin prothrombin complex activity. Famotidine and ranitidine demonstrated either no evidence or minimal evidence of interaction with cytochrome P450 functions, in direct contrast to marked interactions produced by cimetidine. Human studies investigated the potential of an interaction with the coadministration of famotidine and aminopyrine, antipyrine, diazepam, theophylline, phenytoin, and warfarin. Coadministration of famotidine had no effect on the pharmacokinetic variables of theophylline, diazepam, des-methyldiazepam, and phenytoin and no effect on the half-life of antipyrine and aminopyrine or on the prothrombin time ratios associated with warfarin therapy. In those studies using cimetidine as an active control (theophylline, phenytoin, diazepam, and desmethyldiazepam), the variables measured demonstrated marked evidence of interaction with this compound. In summary, famotidine, like ranitidine, demonstrates little or no evidence of interaction with the hepatic cytochrome P450 system. Therefore, it is highly unlikely that coadministration of famotidine and drugs known to be metabolized through the cytochrome P450 system will produce evidence of clinically significant interactions.

Key Words:

• Cimetidine
• cytochrome P450 system
• drug interactions
• drug metabolism
• famotidine
• ranitidine