The present study was undertaken to examine whether the inhibitory effect of diltiazem on the metabolism of propranolol differs from that of cimetidine. Six healthy male volunteers received a single oral dose of 20 mg propranolol with pretreatment with placebo, 60 mg diltiazem, or 400 mg cimetidine three times daily for 4 days. Diltiazem and cimetidine increased the area under the concentration (AUC) of propranolol and its glucuronide. Cimetidine also increased the urinary excretion of propranolol glucuronide. There were no significant differences in the AUC of 4-hydroxypropranolol (4OHPPL) and its conjugates or the urinary excretion of conjugated 4OHPPL. Diltiazem increased the AUC of naphthoxylactic acid (NLA) and the urinary excretion to NLA. After cimetidine pretreatment, there was the trend toward a decrease in the partial metabolic clearance to 4OHPPL and a significant decrease in that of NLA. These results suggest that diltiazem and cimetidine inhibit the oxidation pathways of propranolol in different manners. Cimetidine might inhibit both oxidative pathways to 4OHPPL and NLA, whereas diltiazem might not inhibit the pathway to NLA.