H2-Receptor antagonists may interfere with the pharmacokinetics of concomitantly administered drugs. Our study was designed to investigate whether cimetidine or ranitidine influence the disposition and sedative effect of midazolam. The effect of single oral doses of 800 mg cimetidine, 300 mg ranitidine, or placebo on the steady-state concentrations of midazolam was examined in a randomized crossover study in eight healthy subjects. A midazolam steady-state concentration was achieved by an intravenous bolus (0.05 mg/kg)-infusion (0.025 mg/kg/hr) technique. Plasma concentrations of midazolam, cimetidine, and ranitidine and the pharmacodynamic response to midazolam (choice reaction time, sedation index) were monitored throughout the 10-hour infusion. Cimetidine significantly increased the mean (+/- SD) steady-state plasma concentration of midazolam from 56.7 +/- 7.8 to 71.3 +/- 19.6 ng/ml (P = 0.004). In contrast, the steady-state midazolam concentration after ranitidine dosing (61.8 +/- 6.8 ng/ml) did not differ significantly from that after placebo. No change in choice reaction time or sedation index was detected after cimetidine or ranitidine dosing. Nevertheless, in contrast to ranitidine, the recently advocated once-daily dosing of cimetidine has a potential for hepatic drug interaction that should be considered before its coadministration with drugs that have a narrow therapeutic index.