THE STEREOISOMERS QUININE AND QUINIDINE EXHIBIT A MARKED STEREOSELECTIVITY IN THE INHIBITION OF HEPATOBILIARY TRANSPORT OF CARDIAC-GLYCOSIDES

Background / Aims: Certain basic (cationic) drugs are known to interac t with the hepatic transport, and renal and/or biliary clearance of ca rdia glycosides. The mechanisms behind these interactions are not full y understood, In the present study our was to investigate the effects of the two diastereomers, quinidine and quinine, as well as the calciu m antagonist verapamil, on the hepatobiliary elimination of digoxin an d ouabain in the isolated perfused rat liver. Methods: Livers from mal e, fasting Wistar rats were perfused by recirculation of Krebs-Hensele it bicarbonate buffer supplemented with 1% BSA. Disposition of digoxin or ouabain was studied at an initial perfusion medium concentration ( C-i) of 100 or 10 nmol/l for digoxin and a C-i of 30 mu mol/l for ouab ain. The C-i of quinine, quinidine or verapamil was 50 mu mol/l. Conce ntrations of the drugs in perfusion medium and bile were followed up t o 2 h. Results: A marked reduction in the initial medium disappearance rate of digoxin and ouabain by quinine was found, whereas quinidine d id not affect the hepatic disposition of the cardiac glycosides, The s tereoselective inhibition of digoxin and ouabain clearance by quinine, and not by quinidine, was shown to be due to an effect on the hepatic uptake level rather than on the metabolic conversion and/or the bilia ry excretion steps, An allosteric type of inhibition by the basic drug s, exerted from the inside of the cells, is inferred, The's interactio n may occur at the sinusoidal plasma membrane on the level of multi-sp ecific carrier proteins far cardiac glycosides and cationic drugs, as cloned recently by various groups. Conclusions: A marked stereoselecti ve differences was found in the effect of the stereoisomers quinidine and quinine on the hepatic uptake of digoxin and ouabain, quinine bein g the potent inhibitor.