The effects of cimetidine on the disappearance from plasma, plasma protein binding, tissue distribution, tissue binding in vitro and uptake by erythrocytes of lidocaine were studied in rats. The plasma disappearance of lidocaine after a 10 mg/kg bolus injection was analyzed by a two-compartment open model. In the cimetidine-treated rats (50 mg/kg bolus injection, the plasma total body clearance (Cltot), the volume of distribution at the steady state (Vdss) and the elimination rate constant of the central compartment (kel) of lidocaine decreased by 27, 28 and 32% of those of the non-treated rats, respectively. The plasma concentration of lidocaine at the steady state, after a loading dose (7.62 mg/kg body weight) followed by an infusion (0.16 mg/min/kg), increased from 1.62 to 2.69 micrograms/ml after cimetidine treatment. The tissue-to-plasma concentration ratio (Kp) in spleen, stomach and skin decreased to 64, 62 and 62% of the values of the non-treated rats. In addition, the blood-to-plasma concentration ratio (Rb) decreased by 26% in cimetidine-treated rats. In vitro tissue-to-plasma concentration ratios (Kp, vitro) of lidocaine in spleen, stomach and skin homogenate were decreased to 58, 45 and 68% by cimetidine treatment. In these tissues, the percentage decreases of Kp, vitro agreed with those of Kp determined in vivo. The decrease of Kp by cimetidine treatment may be due to the inhibition of tissue binding of lidocaine. The uptake of lidocaine by erythrocytes was decreased by cimetidine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)