ROLE OF P-GLYCOPROTEIN IN RENAL TUBULAR SECRETION OF DIGOXIN IN THE ISOLATED-PERFUSED RAT-KIDNEY

The mechanism for renal tubular secretion of digoxin as well as its in teraction with quinidine or verapamil were investigated using the isol ated perfused rat kidney. [H-3]Digoxin was instantaneously administere d into the renal artery together with [C-14]inulin and Evans blue-albu min, and renal venous and urinary outflow curves were measured. The ra tio of fractional excretion to filtration fraction for digoxin was 2.4 0 +/- 0.40, indicating involvement of tubular secretion. Quinidine and verapamil decreased the ratio of fractional excretion to filtration f raction in a concentration-dependent manner, and this inhibition was i ndicated to occur at transport from cells to lumen across luminal memb ranes. Neither tetraethylammonium nor p-aminohippurate affected the re nal handling of digoxin. Because ouabain and digitoxose showed no infl uence on the value of fractional excretion to filtration fractions, Na +,K+-ATPase is not involved in the tubular secretion of digoxin. A met abolic inhibitor, 2,4-dinitrophenol, markedly inhibited digoxin secret ion. Agents that bind to P-glycoprotein, such as vinblastine, daunorub icin and reserpine, markedly inhibited the secretion of digoxin. Recen tly, we have found that digoxin is a substrate transported by P-glycop rotein. The findings obtained here support the hypothesis that digoxin is secreted by P-glycoprotein located on the luminal membrane of rena l tubular epithelial cells, and that clinically important interactions with quinidine and verapamil are caused by the inhibition of P-glycop rotein.