Fourteen healthy volunteers received a single i.v. dose of antipyrine (1.2 g) on two occasions, once before and once during cimetidine treatment (300 mg every 6 hr). In a similar manner, 8 subjects received diazepam (10 mg), 11 subjects received acetaminophen (650 mg) and 8 subjects received lorazepam (2 mg), all by the i.v. route, once before and once during cimetidine coadministration. Pharmacokinetic analysis indicated increased antipyrine elimination T1/2 during cimetidine treatment (16.7 vs. 10.9 hr; P less than .001) on the basis of decreased total metabolic clearance (0.46 vs. 0.72 ml/min/kg; P less than .001). Likewise, diazepam T1/2 was increased (58 vs. 39 hr; P less than .01) during cimetidine treatment due to decreased total metabolic clearance (0.42 vs. 0.30 ml/min/kg; P less than .01). In contrast, cimetidine did not alter T1/2 or the clearance of lorazepam (T1/2, 16.8 vs. 15.3 hr; clearance, 1.03 vs 1.07 ml/min/kg) or acetaminophen (T1/2, 2.66 vs. 2.60 hr; clearance, 4.8 vs. 4.5 ml/min/kg), both drugs which undergo conjugative biotransformation. In an animal model used to assess the effect of cimetidine on acetaminophen toxicity, the LD50 of acetaminophen alone in Charles River CD-1 mice was 480 mg/kg (95% confidence interval: 436-528 mg/kg). With simultaneous 75 mg/kg of cimetidine treatment, the LD50 for acetaminophen was significantly increased (P less than .05) to 1020 mg/kg (95% confidence interval: 962-1081 mg/kg). Thus, cimetidine slows the metabolic clearance of antipyrine and diazepam, drugs biotransformed by hepatic oxidation, but does not alter the kinetics of acetaminophen or lorazepam, both metabolized by conjugation. Cimetidine may decrease the toxicity of high-dose acetaminophen by preventing formation of the hepatotoxic oxidative metabolites, although having no effect on conjugation of acetaminophen which yields nontoxic metabolites that are subsequently cleared from the body.