The effect of treatment with omeprazole, a substituted benzimidazole, on the elimination of diazepam and phenytoin was studied in two groups of 8 subjects. Omeprazole given orally in a daily dose of 40 mg over 7 days decreased diazepam plasma clearance from 22.4 +/- 2.8 to 10.1 +/- 1.5 ml/kg X h and prolonged the half-life of diazepam from 36.9 +/- 4.1 to 85.0 +/- 14.7 h. Plasma concentrations of desmethyldiazepam, a diazepam metabolite, were reduced after omeprazole treatment. Omeprazole also reduced the plasma clearance of phenytoin from 25.1 +/- 2.0 to 21.4 +/- 1.8 ml/kg X h and prolonged its half-life from 20.7 +/- 1.9 to 26.3 +/- 2.7 h. Renal excretion of the major metabolite of phenytoin (p-hydroxyphenyl-phenyl-hydantoin) was not changed. Omeprazole did not affect the volume of distribution and the plasma protein binding of either diazepam or phenytoin. In vitro studies with human liver microsomes showed that omeprazole in equimolar concentrations (0.5 mM) was a stronger inhibitor than cimetidine of 7-ethoxycoumarin deethylase activity. These data confirm that omeprazole interferes with the elimination of other drugs by an inhibition of the drug-metabolizing monooxygenase system of the human liver.