Effect of quinidine on digoxin distribution and elimination in guinea pigs

The effect of quinidine on the distribution and elimination of digoxin was examined by comparing the change in the steady-state volume of distribution (Vdss), determined both from in vivo plasma elimination and tissue distribution and in vitro serum binding studies, with that in the total body clearance (CLtot) determined from biliary, renal, and metabolic clearances in guinea pigs. The plasma disappearance of digoxin after a 250-micrograms/kg iv dose followed a triexponential decline in both the control and quinidine-treated guinea pigs. In the quinidine-treated guinea pigs, the pharmacokinetic parameters Vdss and CLtot significantly decreased to approximately half of that for the control guinea pigs. The tissue-to-plasma partition coefficients (Kp) of all tissues studied, i.e. liver, heart, muscle, and brain, at 6 hr after bolus injection of digoxin decreased in the presence of quinidine. The serum free fraction and the plasma-to-blood concentration ratio of digoxin in the therapeutic range did not show a significant alteration in the presence of quinidine. This suggested that the decrease of Kp is due mainly to the inhibition of tissue distribution of digoxin by quinidine. The biliary clearance (CLB) and renal clearance (CLR) also significantly decreased in the presence of quinidine. It was concluded that quinidine caused a inhibition of digoxin in the tissue binding or uptake, which significantly decreased the Kp values of digoxin; this result may explain the significant decrease of Vdss. Moreover quinidine may be the cause of a reduction of biliary, renal, and metabolic clearances, which significantly decrease the CLtot of digoxin.