Clinical implications of drug interactions with the cytochrome P-450 enzyme system associated with omeprazole.
Interactions with the hepatic cytochrome P-450 microsomal enzyme system, as evidenced by statistically significant changes in pharmacokinetic parameters, have been described with some H2-receptor antagonists. Omeprazole is the first of a new class of antisecretory agents inhibiting gastric secretion by blocking hydrogen potassium ATPase. Omeprazole contains a benzimidazole moiety and thus has the potential to interact with the cytochrome P-450 enzyme group. In vitro, in vivo and human clinical studies have assessed whether such an interaction occurs, and the potential clinical consequences, in patients receiving omeprazole therapy. In vitro studies have demonstrated that omeprazole influences O-deethylation and N-demethylation in liver microsomes and the clearance and elimination half-life of antipyrine in isolated perfused liver preparations. Overall, the studies reviewed suggest that omeprazole has a differential affinity toward specific cytochrome P-450 isozymes. In vivo animal studies have demonstrated that omeprazole prolongs pentobarbital sleep times and half-life and decreases [14C]-aminopyrine elimination. Human clinical studies have not demonstrated the "all or none" effect of omeprazole on cytochrome P-450-mediated drug interactions, as is seen with cimetidine. These studies confirm in vitro findings that omeprazole is a differential inhibitor of drug metabolism: interactions have been demonstrated with the model drugs aminopyrine and antipyrine, and the therapeutic drugs diazepam, phenytoin, and warfarin but not with theophylline or propranolol. Although caution should be exercised when initiating omeprazole therapy in patients taking concomitant diazepam, warfarin, and phenytoin, clinically significant drug interactions appear unlikely.
Humphries
T J
TJ
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003975:Diazepam / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D009853:Omeprazole / Q000494:pharmacology*; D010672:Phenytoin / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism; D013806:Theophylline / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism
D000632:Aminopyrine; D014859:Warfarin; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D013806:Theophylline; D009853:Omeprazole; D003975:Diazepam; D000983:Antipyrine