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  • Title: Digoxin-cyclosporin A interaction: modulation of the multidrug transporter P-glycoprotein in the kidney.
    Author: Okamura N, Hirai M, Tanigawara Y, Tanaka K, Yasuhara M, Ueda K, Komano T, Hori R.
    Journal: J Pharmacol Exp Ther; 1993 Sep; 266(3):1614-9. PubMed ID: 8103797.
    Abstract:
    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 transepithelial 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 microM 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 microM 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.
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