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 interaction with quinidine or verapamil were investigated using the isolated perfused rat kidney. [3H]Digoxin was instantaneously administered into the renal artery together with [14C]inulin and Evans blue-albumin, and renal venous and urinary outflow curves were measured. The ratio of fractional excretion to filtration fraction for digoxin was 2.40 +/- 0.40, indicating involvement of tubular secretion. Quinidine and verapamil decreased the ratio of fractional excretion to filtration fraction in a concentration-dependent manner, and this inhibition was indicated to occur at transport from cells to lumen across luminal membranes. Neither tetraethylammonium nor p-aminohippurate affected the renal handling of digoxin. Because ouabain and digitoxose showed no influence on the value of fractional excretion to filtration fractions, Na+,K(+)-ATPase is not involved in the tubular secretion of digoxin. A metabolic inhibitor, 2,4-dinitrophenol, markedly inhibited digoxin secretion. Agents that bind to P-glycoprotein, such as vinblastine, daunorubicin and reserpine, markedly inhibited the secretion of digoxin. Recently, we have found that digoxin is a substrate transported by P-glycoprotein. The findings obtained here support the hypothesis that digoxin is secreted by P-glycoprotein located on the luminal membrane of renal tubular epithelial cells, and that clinically important interactions with quinidine and verapamil are caused by the inhibition of P-glycoprotein.
Hori
R
R
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
Okamura
N
N
Aiba
T
T
Tanigawara
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D004077:Digoxin / Q000378:metabolism* / Q000652:urine; D066298:In Vitro Techniques; D007444:Inulin / Q000493:pharmacokinetics; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D010477:Perfusion; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D014316:Tritium; D004077:Digoxin; D007444:Inulin; D014700:Verapamil; D011802:Quinidine