The effects of pretreatment with cimetidine (1 gm daily for 3 days) on the disposition of lidocaine were examined in 18 healthy subjects, seven of whom were chronic cigarette smokers. Each subject received separate oral (200 mg) and intravenous (75 or 100 mg) doses of lidocaine before and after cimetidine. After cimetidine, lidocaine apparent oral clearance (Clo) reduced 42% +/- 7%; oral bioavailability increased 35% +/- 10%; and systemic clearance (Cls) and volume of distribution at steady-state (Vdss) decreased 21% +/- 6% and 20% +/- 7%. Elimination t 1/2 was unchanged. Calculated values for Cls after cimetidine based on reduction in Clo and consequent decrease in hepatic extraction ratio correlated significantly with observed values for Cls (r = 0.67). Women had larger Vdss (64% +/- 19%), longer t 1/2 (50% +/- 18%), and greater oral lidocaine bioavailability (63% +/- 29%) than did men. There was no sex difference in and no influence of cigarette smoking on the effects of cimetidine. The results indicate that cimetidine reduces metabolic clearance of lidocaine. The consequent reduced hepatic extraction explains the observed reduction in Cls.