Cimetidine reduced liver blood flow and the systemic clearance of drugs, such as propranolol, that are highly extracted by the liver. In a randomized placebo-controlled study, we examined the influence of cimetidine, 300 mg four times daily for 1 d, on the disposition of lidocaine, 1 mg/kg body weight by a 10-minute intravenous infusion. Cimetidine reduced the systemic clearance of lidocaine from 766 +/- 50 mL/min to 576 +/- 47 mL/min (p less than 0.05); the apparent volume of distribution at steady-state and the degree of plasma protein binding of lidocaine also were decreased. Five of the six subjects noted lidocaine toxicity during the cimetidine infusion in contrast to one subject on the placebo day. The peak lidocaine concentration (mean +/- SE) was 50% +/- 10% higher when subjects received cimetidine. This study provides additional evidence that the effect of cimetidine on the elimination of other drugs has multiple factors, and shows a previously unrecognized mechanism, involving altered initial drug distribution, whereby the interaction of cimetidine with other drugs may cause toxicity.