Effects of basic drugs on the hepatic transport of cardiac glycosides in rats

Abstract The effects of some basic and acidic drugs on the hepatic uptake of digoxin and ouabain were studied in isolated rat hepatocytes. Digoxin accumulated against a concentration gradient, and its initial uptake was energy- and temperature-dependent. Digoxin competitively inhibited the uptake of ouabain ( K i = 1.3 μ M), which was reported to be transported by a carrier-mediated active transport system. All basic drugs tested (verapamil, dipyridamole, amiodarone, nifedipine, diltiazem, ajmaline, chlorpromazine, imipramine, disopyramide, quinidine, procainamide, propranolol and lidocaine: 50 μM) except for procainamide, propranolol and lidocaine significantly (P K i = 88 μ M). These basic drugs had no effect on the permeability of the cells assessed by the trypan blue exclusion test and succinate-stimulated oxygen consumption. But carbonylcyanide- m -chlorophenyl hydrazone-stimulated oxygen consumption decreased in the presence of some basic drugs and correlated with their inhibitory effects on digoxin uptake. Therefore, one of the mechanisms of the inhibitory effects of these drugs on digoxin uptake was the inhibition of oxidative phosphorylation. These basic drugs had no effect on the microtubular system, which was assessed by the measurement of tubulin polymerization and colchicine binding to tubulin. The results of our study suggested that many basic drugs have a potential to inhibit the hepatocellular uptake of cardiac glycosides.