Cyclosporin and quinidine inhibition of renal digoxin excretion: Evidence for luminal secretion of digoxin

We studied the in vivo luminal and contraluminal uptake of [³H] digoxin in dog kidney using the single-pass multiple indicator dilution method. A bolus tracer of ¹²⁵I-albumin (plasma reference), creatinine, or L-[¹⁴C]glucose [extracellular reference (ecf)] and [³H]digoxin (or [³H]ouabain) was injected into the left renal artery, and timed serial samples were collected from the left renal vein (basolateral uptake) and left and right ureters (luminal uptake). [³H]ouabain was excreted solely by filtration and exhibited saturable and irreversible binding at the basolateral surface. Uptake of [³H] digoxin across the basolateral membrane was large and nonsaturable. Despite urine flow-dependent reabsorption and ∼20% protein binding, the urine recovery ratio for [³H]-digoxin/glomerular (ecf) marker was 0.97 ± 0.04 (n = 29), indicating net digoxin secretion. After intravenous infusions of cyclosporin in Cremophor EL (0.5-3.5 μM), the urine recovery ratio decreased in a dose-dependent manner from control values of 1.13 ± 0.06 (n = 12) to 0.62 ± 0.03 (n = 14). There was no change in the relative renal vein recovery. Left renal artery infusion of quinidine (37.5 μg·min^-1·kg^-1) decreased the relative urine recovery of [³H]digoxin by 46% (n = 6) but had no effect on postglomerular extraction. Cyclosporin and quinidine are known inhibitors of P-glycoprotein. But digoxin did not compete with [³H]azidopine for binding in rat brush-border membranes or membranes prepared from the multidrug-resistant cell line CHRC5. The exact mechanism for renal digoxin secretion remains to be determined, but our results point to a luminal localization of this secretory system.