Digoxin-cyclosporin A interaction: modulation of the multidrug transporter P-glycoprotein in the kidney.
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.
Okamura
N
N
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
Hirai
M
M
Tanigawara
Y
Y
Tanaka
K
K
Yasuhara
M
M
Ueda
K
K
Komano
T
T
Hori
R
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004247:DNA / Q000235:genetics; D004077:Digoxin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D004077:Digoxin; D016572:Cyclosporine; D004247:DNA