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.
