STEREOSELECTIVE INHIBITION BY THE DIASTEREOMERS QUINIDINE AND QUININEOF UPTAKE OF CARDIAC-GLYCOSIDES INTO ISOLATED RAT HEPATOCYTES

The pharmacokinetic interaction between quinidine and digoxin in patie nts is well-known, in general requiring a dose reduction of digoxin in patients concomitantly treated with quinidine. Quinine, the diastereo mer of quinidine, has not been as extensively studied in this respect. In addition to an interaction with the renal clearance of digoxin by quinidine, both diastereomers have been reported to inhibit the biliar y clearance of digoxin in man. To further investigate the mechanisms o f these hepatobiliary transport interactions at the cellular level, we compared the effects of quinidine and quinine, as well as of the calc ium antagonist verapamil, on the uptake of digoxin and ouabain in isol ated rat hepatocytes. Initial uptake rates of digoxin and ouabain were determined in the presence of various concentrations of quinine and q uinidine. A concentration dependent inhibition of the cellular uptake of both cardiac glycosides by quinine and quinidine was found, quinine being a more potent inhibitor than quinidine. Our results indicate a stereoselective inhibition of the hepatocellular uptake by the two dia stereomers quinidine and quinine, the latter being about equipotent to verapamil. This unequal inhibitory potency of the two basic drugs was detected earlier in oocyte studies with the cloned organic cation tra nsporter OCT1.