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.