FACTORS AFFECTING THE RENAL EXCRETION OF DRUGS

对于某些器官，特别是肝脏， 了解生理和病理的影响 影响器官清除的因素已经出现。 这一信息 为预测未来的影响力提供了有力的依据。 药物给药后的药理学和病理学干预 养生法 与此相反，定量描述的影响， 缺乏对肾脏药物清除的这些干预。 的 拟议的研究将试图弥补这一缺陷， 定量肾血流量、药物- 蛋白质结合、药物浓度、老化等 实验疾病状态对模型肾清除率的影响 在分离的灌流大鼠肾脏制备物（IPRK）中的底物。 一种IPRK制剂，灌注有红细胞， 灌注液，将用于研究p- 氨基马尿酸、氯噻嗪、呋塞米和头孢尼西。 这些模型底物具有一系列的活性亲和力， 肾小管分泌，但不显著重吸收，或 由肾脏代谢。 灌注液流和绑定（通过 白蛋白浓度）将在宽范围内变化， 通过以下方法定量测定对各底物肾清除率的影响 建立了器官消除模型。 通过改变 灌注液中每种底物的浓度，并通过检查 基质的组合，多个 给定底物的小管分泌中的转运蛋白将被 探讨了 这些活性底物的肾清除率 肾小管分泌和洋地黄毒苷，一种底物， 肾小管重吸收，但不是主动分泌，将在 从高龄大鼠（26-30个月）或 实验诱导的急性肾衰竭、肥胖（饮食性 诱导的）和糖尿病（链脲佐菌素诱导的）。 急性肾衰竭 将通过给予甘油、硝酸铀酰和 叶酸和通过热缺血。 对肾脏的研究 衰老的老鼠，或者那些患有实验性疾病的老鼠，将测试 常用的治疗原则是通过 肾小管分泌和重吸收的变化与 肾小球滤过率的变化。

For some organs, particularly the liver, a quantitative understanding of the effect of physiological and pathological factors upon organ clearance has emerged. This information has provided a powerful basis for predicting the influence of pharmacological and pathological interventions upon drug dosing regimens. In contrast, a quantitative description of the impact of these interventions upon renal drug clearance is lacking. The proposed research will attempt to remedy this shortcoming by quantitating the effect of changes in renal blood flow, drug- protein binding, drug concentration, aging, and several experimental disease states upon the renal clearance of model substrates in an isolated perfused rat kidney preparation (IPRK). An IPRK preparation, perfused with an erythrocyte containing perfusate, will be employed to study the renal clearance of p- aminohippuric acid, chlorothiazide, furosemide and cefonicid. These model substrates have a range of affinities for active tubular secretion but are not significantly reabsorbed or metabolized by the kidney. Perfusate flow and binding (via albumin concentration) will be varied over a wide range and their influence on the renal clearance of each substrate quantified via established models of organ elimination. By varying the concentration of each substrate in the perfusate and by examining combinations of substrates, the involvement of multiple transporters in the tubular secretion of a given substrate will be explored. The renal clearance of these substrates of active tubular secretion and that of digitoxin, a substrate for passive tubular reabsorption but not active secretion, will be studied in kidneys isolated from rats of advanced age (26-30 month) or with experimentally induced acute renal failure, obesity (dietary induced) and diabetes (steptozotocin induced). Acute renal failure will be induced via administration of glycerol, uranyl nitrate and folate and via warm ischaemia. The study of the kidneys of senescent rats, or those with experimental disease, will test the commonly used therapeutic principal that drug elimination via tubular secretion and reabsorption changes in direct proportion to changes in glomerular filtration rate.