title: Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney.
abstract: 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.
authors.affiliation: Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Hori
authors.forename: N
authors.initials: N
authors.lastname: Okamura
authors.forename: T
authors.initials: T
authors.lastname: Aiba
authors.forename: Y
authors.initials: Y
authors.lastname: Tanigawara
mesh_terms: 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
chemical_list: 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