Effects of cimetidine on quinidine distribution and tissue pH in rats

To elucidate the mechanism(s) of the decrease of the volume of distribution at steady state (Vdss) and the tissue-to-plasma concentration ratio (Kp) of quinidine after cimetidine treatment, the following were studied; (1) the effect of cimetidine on the tissue binding of quinidine in vitro, (2) the non-linear tissue distribution of quinidine and (3) the effect of cimetidine on tissue pH. The in vitro binding of quinidine to rat tissue homogenates was not affected by cimetidine treatment. The tissue distribution of quinidine in rats was linear from 1 to 5 micrograms/ml of plasma concentration except for lung. The plasma disappearance of 5,5-dimethyl-2,4-oxazolidinedione (DMO) after a 200 mg/kg intravenous injection was fitted to a two compartment open model. In the cimetidine-treated rats (50 mg/kg), the pharmacokinetic parameters of DMO, such as the plasma total body clearance (Cltot), Vdss and the rate constant at the terminal phase (beta) increased to 230, 110 and 210% of those of the non-treated rats, respectively. The intracellular pH calculated by Kp of DMO increased significantly in liver, spleen, intestine, brain, muscle and skin. This suggests that cimetidine decreased the tissue-to-plasma pH partition coefficient (q) of unbound quinidine in several tissues. The decreases of Vdss and Kp of quinidine by cimetidine was attributed to the decrease of q resulting from the increase of tissue pH.