RENAL SECRETION OF VINBLASTINE, VINCRISTINE AND COLCHICINE IN-VIVO

The MDR1 gene product, P-glycoprotein, has been localized to the apica l 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 an d colchicine, by using the single pass multiple indicator dilution met hod under control conditions and in the presence of increasing concent rations of cyclosporin A, a potent inhibitor of P-glycoprotein, A bolu s of [I-125]albumin (plasma reference), L-[C-14]glucose (extracellular and glomerular reference) and tracer H-3-substrate was injected into the left renal artery of anesthetized dogs and timed serial samples we re collected from the left renal vein and left and right ureters. In a single pass, approximately 38, 13 and 8% of [H-3]vinblastine, [H-3] v incristine and [H-3]colchicine, respectively, was extracted from the p ostglomerular circulation. Drug binding to plasma proteins was determi ned to be 81% for [H-3]vinblastine, 71% for [H-3] vincristine and 23% for [H-3]colchicine. Despite the high degree of drug protein binding, the urine recoveries of [H-3]vinblastine, [H-3]vincristine and [H-3]co lchicine relative to L-[C-14]glucose were 0.75 +/- 0.06, 0.69 +/- 0.06 and 0.94 +/- 0.02, confirming net secretion of each of these substrat es. Infusion of cyclosporin A (0.1-5 mu M) significantly decreased the urine recovery of [H-3] vinblastine and [H-3]vincristine relative to L-[C-14]glucose in a dose-dependent manner. The renal excretion of [H- 3]colchicine was not affected by cyclosporin A at the concentrations t ested (1-2 mu M). The evidence suggests that net secretion of [H-3]vin blastine and [H-3]vincristine occurs across the luminal membrane of th e renal cell. Inhibition by cyclosporin implicates luminal P-glycoprot ein as the most likely mechanism for secretion.