ROLE OF P GLYCOPROTEIN IN CATIONIC RENAL TUBULAR SECRETION

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The research mission is to develop methodologies to quantify glomerular and tubular function. Once established, we hope to use these tools to assess the influence of aging, gender and various disease processes such as diabetic nephropathy, hypertension, glomerulonephritis, hepatic cirrhosis and HIV on renal function. The aim of this research project is to test the hypothesis that p-glycoprotein transport is a major component of the renal tubular excretion of famotidine. This will be accomplished in a randomized study involving administration of intravenous cimetidine and famotidine alone and in combination with oral itraconazole to healthy volunteers with normal renal function. Both cimetidine and famotidine undergo extensive tubular secretion by cationic pathway. In vitro studies suggest that cimetidine is transported from renal tubular cells into the urine by p-glycoprotein transport. Thus, it will be utilized here as a positive control; its renal excretion should decrease in the presence of itraconazole, a potent in vitro inhibitor of p-glycoprotein. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and filtration fraction (FF) will be monitored throughout each study using the widely accepted method of continuous iothalamate and PAH renal clearances. The urinary excretion rate and GFR will be used to calculate the rate of tubular secretion of cimetidine and famotidine when given alone and in the presence of itraconazole.