Effects of cimetidine on quinidine distribution in rats

The effects of cimetidine on the time course of plasma concentration, plasma protein binding and tissue distribution of quinidine were studied in rats. The plasma disappearance of quinidine after a 25 mg/kg intravenous injection was fitted to a two compartment open model. In the cimetidine-treated rats (50 mg/kg), the pharmacokinetic parameters of quinidine, such as the plasma total body clearance (Cltot), the volume of distribution at steady state (Vdss) and the elimination rate constant of the central compartment (kel) decreased to 62, 60 and 73%, respectively of those of the non-treated rats. The plasma concentration of quinidine at steady state, after an intravenous injection (20 mg/kg body weight) followed by a constant rate infusion (0.2 mg/min/kg), increased from 3.02 to 5.11 micrograms/ml after cimetidine treatment. The tissue-to-plasma concentration ratio (Kp) of heart, brain and muscle, determined in homogenates at steady state, decreased after cimetidine treatment. The effect of cimetidine lasted several hours after a cimetidine bolus intravenous injection. These decreases of Kp could satisfy quantitatively the decrease of Vdss. It may be concluded that the decrease of Vdss was due to the inhibition of tissue distribution (binding and/or partition to tissue components) of quinidine by cimetidine treatment.