EFFECTS OF CIMETIDINE ON QUINIDINE DISTRIBUTION IN RATS

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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 (Cl_<rot>), the volume of distribution at steady state (V_<dss>) and the elimination rate constant of the central compartment (k_<el>) 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 μg/ml after cimetidine treatment. The tissue-to-plasma concentration ratio (K_p) 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 K_p could satisfy quantitatively the decrease of V_<dss>. It may be concluded that the decrease of V_<dss> was due to the inhibition of tissue distribution (binding and/or partition to tissue components) of quinidine by cimetidine treatment.
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