AGING MEDIATED CHANGES IN RENAL EXCRETION OF ORGANIC ANIONS

本研究的广泛长期目标是表征衰老对肾脏药物排泄的影响。尽管已经确定，随着年龄的增长，肾功能会发生解剖和生理变化，但关于年龄对肾脏排泄药物的各个机制（过滤、分泌和重吸收）的不同影响的数据很少。本研究的第一个具体目的是建立离体大鼠肾穿孔模型，作为研究衰老对生理肾功能和肾清除率影响的有用工具。建立IPK作为老年受试者肾脏药物分布的模型，将允许衰老和影响肾脏药物排泄的众多因素之间的相关性。该研究的第二个目的是测试“全肾单位假说”的有效性，该假说假设继发于衰老或疾病的肾小球滤过减少伴随着分泌和重吸收的平行减少。尽管这一假设是根据肾小球滤过率（GFR）进行剂量调整的基础，但文献中的报告表明，在OFR降低的情况下，某些药物的肾小管分泌可以维持。研究衰老对肾脏排泄的对氨基马尿酸盐和乙酰唑胺，对比程度的肾脏提取化合物的影响，将允许肾脏的过滤和分泌机制之间的线性评估。这些发现可能挑战目前老年患者中基于GFR的药物给药指南，并可能降低该患者人群中药物相关发病率。

The broad long term objective of this research is to characterize the effects of aging on renal drug excretion. Although it is well established that becoming older is accompanied by anatomic and physiologic changes in renal function, there is a paucity of data regarding the differential effects of aging on the individual mechanisms of renal excretion of medications: filtration, secretion and reabsorption. The first specific aim of the research is to establish the isolated perfiised rat kidney (IPK) model as a useful tool for studying the effects of aging on physiologic renal function and renal clearance. Establishing the IPK as a model of renal drug disposition in geriatric subjects would allow correlation between aging and the numerous factors which affect renal drug excretion. A second aim of the research is to test the validity of the "Whole Nephron Hypothesis" which assumes that reductions in glomerular filtration secondary to aging or disease are accompanied by parallel reductions in secretion and reabsorption. Whereas this hypothesis is the basis for making dosage adjustments based on glomerular filtration rate (GFR), reports in the literature suggest that tubular secretion of certain medications can be maintained in the presence of decreased OFR. Studying the effects of aging on the renal excretion para-aminohippurate and acetazolamide, compounds of contrasting degrees of renal extraction, will permit assessment of the linearity between filtration and secretory mechanisms of the kidney. These findings could challenge present guidelines for GFR-based dosing of medications in geriatric patients and possibly reduce the incidence of drug-related morbidity in this patient population.