Renal secretion of vinblastine, vincristine and colchicine in vivo.
The MDR1 gene product, P-glycoprotein, has been localized to the apical surface of the renal proximal tubule, but its functional role in the kidney is unknown. We studied renal luminal and antiluminal uptake of three known substrates of P-glycoprotein: vinblastine, vincristine and colchicine, by using the single pass multiple indicator dilution method under control conditions and in the presence of increasing concentrations of cyclosporin A, a potent inhibitor of P-glycoprotein. A bolus of [125I]albumin (plasma reference), L-[14C]glucose (extracellular and glomerular reference) and tracer 3H-substrate was injected into the left renal artery of anesthetized dogs and timed serial samples were collected from the left renal vein and left and right ureters. In a single pass, approximately 38, 13 and 8% of [3H]vinblastine, [3H] vincristine and [3H]colchicine, respectively, was extracted from the postglomerular circulation. Drug binding to plasma proteins was determined to be 81% for [3H]vinblastine, 71% for [3H] vincristine and 23% for [3H]colchicine. Despite the high degree of drug protein binding, the urine recoveries of [3H]vinblastine, [3H]vincristine and [3H]colchicine relative to L-[14C]glucose were 0.75 +/- 0.06, 0.69 +/- 0.06 and 0.94 +/- 0.02, confirming net secretion of each of these substrates. Infusion of cyclosporin A (0.1-5 microM) significantly decreased the urine recovery of [3H] vinblastine and [3H]vincristine relative to L-[14C]glucose in a dose-dependent manner. The renal excretion of [3H]colchicine was not affected by cyclosporin A at the concentrations tested (1-2 microM). The evidence suggests that net secretion of [3H]vinblastine and [3H]vincristine occurs across the luminal membrane of the renal cell.(ABSTRACT TRUNCATED AT 250 WORDS)
de Lannoy
I A
IA
Department of Medicine, University of Toronto, Ontario, Canada.
Mandin
R S
RS
Silverman
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003078:Colchicine / Q000493:pharmacokinetics*; D016572:Cyclosporine / Q000494:pharmacology; D004285:Dogs; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D014747:Vinblastine / Q000493:pharmacokinetics*; D014750:Vincristine / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D014750:Vincristine; D014747:Vinblastine; D016572:Cyclosporine; D003078:Colchicine