Quinine impairs quinidine clearance in rat perfused liver

We have examined the disposition of the cinchona alkaloids quinine and quinidine in the rat recirculating isolated perfused liver preparation. When administered as separate 1 mg doses, the hepatic clearances of quinine and quinidine were similar to the hepatic perfusate rate of 10 mL min-1. When 1 mg of each was administered simultaneously, mean hepatic clearance of quinine was unchanged (9.00 +/- 2.20 mL min-1 separate dosage, n = 7; 6.87 +/- 1.77 mL min-1 simultaneous dosage, n = 7; P > 0.05). By contrast, mean hepatic clearance of quinidine was reduced significantly by concomitant quinine (10.6 +/- 1.72 mL min-1 separate dosage, n = 7; 4.82 +/- 1.25 mL min-1 simultaneous dosage, n = 7; P < 0.05). There was no significant difference in volumes of distribution when each alkaloid was administered separately (131 +/- 46 mL quinine, 129 +/- 21 mL quinidine; P > 0.05) but concomitant quinine administration increased quinidine volume of distribution to 169 +/- 30 mL (P < 0.05). Four further experiments with simultaneous dosages of 0.5 mg of each alkaloid produced similar findings, indicating that the interactions did not derive from nonlinear drug disposition.