ROLE OF P GLYCOPROTEIN IN CATIONIC RENAL TUBULAR SECRETION

研究任务是开发量化肾小球和肾小管功能的方法。一旦建立，我们希望使用这些工具来评估年龄、性别和各种疾病过程对肾功能的影响，如糖尿病肾病、高血压、肾小球肾炎、肝硬变和艾滋病毒。该研究项目的目的是验证P-糖蛋白转运是法莫替丁肾小管排泄的主要成分的假设。这将在一项随机研究中完成，包括单独静脉注射西咪替丁和法莫替丁，以及联合口服伊曲康唑给肾功能正常的健康志愿者。西咪替丁和法莫替丁都通过阳离子途径进行广泛的肾小管分泌。体外研究表明，西咪替丁通过P-糖蛋白转运从肾小管上皮细胞进入尿液。因此，在这里，它将被用作阳性对照；在伊曲康唑存在下，它的肾脏排泄应该会减少，伊曲康唑是一种有效的P-糖蛋白体外抑制剂。在每项研究中，肾小球滤过率(GFR)、有效肾血浆流量(ERPF)和滤过分数(FF)将使用广泛接受的连续异硫氰酸酯和PAH肾脏清除方法进行监测。尿排泄率和肾小球滤过率将被用来计算单独给药和伊曲康唑存在时西咪替丁和法莫替丁的肾小管分泌率。

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.