FACTORS AFFECTING THE RENAL EXCRETION OF DRUGS

对于某些器官，特别是肝脏， 对生理学和病理学影响的认识 影响器官清除的因素已经出现。此信息具有 为预测影响提供了有力的依据 给药后的药理和病理干预 养生法。相比之下，定量描述 缺乏对肾脏药物清除的干预。这个 拟议的研究将试图通过以下方式来弥补这一缺陷 量化肾血流变化的影响，药物- 蛋白质结合、药物浓度、衰老等 实验性疾病状态对模型肾清除的影响 分离灌流大鼠肾脏制剂(IPRK)中的底物。 一种IPRK制剂，用含有以下物质的红细胞灌流 灌流液，将被用来研究p-羟色胺的肾清除。 氨基马尿酸、氯噻嗪、速尿和头孢尼西。 这些模型底物对Active具有一系列亲和力 但肾小管分泌物不会被显著重吸收或 由肾脏代谢的。灌流和结合(通孔 白蛋白浓度)将在很大范围内变化，其 不同底物对肾清除率的影响 建立了器官消除的模型。通过改变 灌流液中每种底物的浓度和通过检查 底物的组合，涉及多个 特定底物的肾小管分泌物中的转运体 探索过了。这些活性底物对肾脏的清除作用 小管分泌物和被动作用底物地黄毒素的分泌物 肾小管重吸收，但不是主动分泌，将在 分离高龄(26-30个月)大鼠肾脏或 实验诱导的急性肾功能衰竭、肥胖(饮食 糖尿病(链脲佐菌素诱导)。急性肾功能衰竭 将通过甘油，硝酸铀酰和 叶酸和温性脑缺血。对儿童肾脏的研究 衰老的老鼠，或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药物消除 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.