CYCLOSPORINE AND QUINIDINE INHIBITION OF RENAL DIGOXIN EXCRETION - EVIDENCE FOR LUMINAL SECRETION OF DIGOXIN

被引:44
作者
DELANNOY, IAM
KOREN, G
KLEIN, J
CHARUK, J
SILVERMAN, M
机构
[1] UNIV TORONTO,DEPT MED,MED RES COUNCIL GRP MEMBRANE BIOL,MED SCI BLDG,RM 7226,TORONTO M5S 1A8,ONTARIO,CANADA
[2] HOSP SICK CHILDREN,RES INST,DIV CLIN PHARMACOL,TORONTO M5G 1X8,ONTARIO,CANADA
[3] HOSP SICK CHILDREN,DEPT PEDIAT,TORONTO M5G 1X8,ONTARIO,CANADA
来源
AMERICAN JOURNAL OF PHYSIOLOGY | 1992年 / 263卷 / 04期
关键词
DIGOXIN TRANSPORT IN KIDNEY; OUABAIN EXCRETION IN KIDNEY; MULTIPLE INDICATOR DILUTION; PHOTOAFFINITY LABELING OF P-GLYCOPROTEIN;
D O I
10.1152/ajprenal.1992.263.4.F613
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
We studied the in vivo luminal and contraluminal uptake of [H-3]digoxin in dog kidney using the single-pass multiple indicator dilution method. A bolus tracer of I-125-albumin (plasma reference), creatinine, or L-[C-14]glucose [extracellular reference (ecf)] and [H-3]digoxin (or [H-3]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). [H-3]ouabain was excreted solely by filtration and exhibited saturable and irreversible binding at the basolateral surface. Uptake of [H-3]digoxin across the basolateral membrane was large and nonsaturable. Despite urine flow-dependent reabsorption and approximately 20% protein binding, the urine recovery ratio for [H-3]-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 muM), 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 mug.min-1.kg-1) decreased the relative urine recovery of [H-3]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 [H-3]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.
引用
收藏
页码:F613 / F622
页数:10
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