PROTEIN BINDING/ORGAN PERFUSION AND RENAL DRUG TRANSPORT

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The relationship between the mathematical description and biological determinants of renal drug clearance has not been well defined nor adequately verified. In particular, the effect of protein binding and renal blood flow on the secretory transport of drug is still considered in a descriptive rather than quantitative manner. Therefore, the primary objectives of the proposed studies are 1) to gain a better understanding of the role of protein binding on the renal transport kinetics of two model compounds (chlorothiazide and cefonicid), 2) to determine whether the rate of renal tubular secretion for the above is a function of the free or total plasma concentrations, and 3) to study, in a quantitative manner, the effect of changes in organ perfusion on the renal and secretory clearances of three model compounds (furosemide, chlorothiazide, and cefonicid). Drug studies will be performed using an isolated, perfused rat kidney preparation. Various combinations of bovine serum albumin and dextran will be used in order to produce a wide range of values for the protein binding studies. Angiotensin II, a powerful vasoconstrictor hormone of afferent and efferent arterioles in the kidney will be used to alter renal perfusate flow in the organ perfusion studies. Furosemide, chlorothiazide, and cefonicid will be assayed by HPLC, inulin by liquid scintilation counting, glucose by colorimetry, and sodium by flame photometry. The protein binding of drug in perfusate will be determined using equilibrium dialysis techniques. The relationship between renal drug excretion and protein binding for chlorothiazide and cefonicid will be evaluated using equations which represent experimentally separable models and their inherent assumptions. The precise nature of these relationships will allow one to determine whether or not, and to what extent, the renal extraction of these two compounds is limited to the recirculating free drug. Experiments with and without angiotensin II should help to elucidate the degree of sensitivity and mechanism of flow-induced changes in the renal excretion of furosemide, chlorothiazide, and cefonicid. These studies will provide insight into the effect of individual variations in renal transport activity, pharmacokinetic interactions, and disease states on renal drug elimination. In doing so, more rational guidelines will be provided for a prior dosage adjustments of those therapeutic agents whose renal excretion is sensitive to changes in protein binding or renal blood flow.