Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney

R. Hori, N. Okamura, T. Aiba, Yusuke Tanigawara

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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.

Original languageEnglish
Pages (from-to)1620-1625
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume266
Issue number3
Publication statusPublished - 1993
Externally publishedYes

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Digoxin
P-Glycoprotein
Kidney
p-Aminohippuric Acid
2,4-Dinitrophenol
Evans Blue
Daunorubicin
Tetraethylammonium
Membranes
Inulin
Vinblastine
Reserpine
Renal Artery
Ouabain
Albumins
Epithelial Cells

ASJC Scopus subject areas

  • Pharmacology

Cite this

Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. / Hori, R.; Okamura, N.; Aiba, T.; Tanigawara, Yusuke.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 266, No. 3, 1993, p. 1620-1625.

Research output: Contribution to journalArticle

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