PT  - JOURNAL ARTICLE
AU  - N Okamura
AU  - M Hirai
AU  - Y Tanigawara
AU  - K Tanaka
AU  - M Yasuhara
AU  - K Ueda
AU  - T Komano
AU  - R Hori
TI  - Digoxin-cyclosporin A interaction: modulation of the multidrug transporter P-glycoprotein in the kidney.
DP  - 1993 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1614--1619
VI  - 266
IP  - 3
4099  - http://jpet.aspetjournals.org/content/266/3/1614.short
4100  - http://jpet.aspetjournals.org/content/266/3/1614.full
SO  - J Pharmacol Exp Ther1993 Sep 01; 266
AB  - 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.