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 approximately 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 microM), 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 micrograms.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.
De Lannoy
I A
IA
Department of Medicine, University of Toronto, Ontario, Canada.
Koren
G
G
Klein
J
J
Charuk
J
J
Silverman
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004077:Digoxin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000652:urine; D004285:Dogs; D005260:Female; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D010042:Ouabain / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D008562:Membrane Glycoproteins; D010042:Ouabain; D004077:Digoxin; D016572:Cyclosporine; D011802:Quinidine