Digoxin-cyclosporin A interaction: Modulation of the multidrug transporter P-glycoprotein in the kidney

N. Okamura, M. Hirai, Y. Tanigawara, K. Tanaka, M. Yasuhara, K. Ueda, T. Komano, R. Hori

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45 Citations (Scopus)


The mechanism of a renal tubular digoxin-cyclosporin A interaction was elucidated using a kidney epithelial cell line and the isolated perfused rat kidney. The cells expressed an excess amount of human P-glycoprotein on the apical membranes by transfection with MDR1 cDNA. Cyclosporin A inhibited the trans-epithelial transport of digoxin mediated by human P-glycoprotein; net basal-to-apical transport across the cell monolayer was 22.8, 21.2, 6.61 and 0.91 pmol/mg of protein/3 hr in the presence of 0, 1, 5 and 10 μM cyclosporin A, respectively. Cyclosporin A also reduced the renal tubular secretion of digoxin by the kidney. The ratio of fractional excretion/filtration fraction for digoxin was 2.88 ± 0.71 (mean ± S.D.) in the control, and this was decreased to 1.21 ± 0.09 and 1.05 ± 0.13 in the presence of 1 and 5 μM cyclosporin A, respectively. Because no signs of acute nephrotoxicity were observed, a direct effect of cyclosporin A accounted for the reduced secretion. On the other hand, digoxin did not affect cyclosporin A transport by P-glycoprotein. These findings indicate that serum concentrations of digoxin in patients should be carefully monitored when administered concurrently with cyclosporin A. The present transepithelial transport system using the transfectant cells is a simple and useful screening system for predicting drug interactions that can occur in a clinical situation.

Original languageEnglish
Pages (from-to)1614-1619
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - 1993 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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