PROTEIN BINDING/ORGAN PERFUSION AND RENAL DRUG TRANSPORT

数学描述与数学描述之间的关系 肾脏药物清除的生物决定因素一直不是很好 没有定义，也没有得到充分的验证。尤其是， 蛋白结合和肾血流对肾小球蛋白分泌转运的影响 药物仍然被认为是描述性的，而不是定量的 举止。因此，拟议的主要目标是 研究是1)更好地了解蛋白质的作用 两种模型化合物对肾脏转运动力学的结合作用 (氯噻嗪和头孢尼西)，2)测定缓释率 肾小管分泌物的上述是一种游离的功能 或血浆总浓度，以及3)进行定量研究 方式，器官血流灌注的变化对肾脏和 三种模型化合物(速尿，速尿， 氯噻嗪和头孢尼西)。 药物研究将使用隔离的灌流大鼠进行 肾脏准备。牛血清的各种组合 将使用白蛋白和葡聚糖来产生广泛的 蛋白质结合研究的价值。血管紧张素II，a 强效血管收缩激素的传入和传出 肾脏中的小动脉将被用来改变肾脏的灌流。 在器官灌流研究中。速尿、氯噻嗪和 用高效液相色谱法测定头孢尼西的含量，用液闪法测定菊粉的含量 计数、比色法测定葡萄糖、火焰测定钠 测光学。药物在灌流液中的蛋白质结合将是 采用平衡透析法测定。 肾脏药物排泄与蛋白质结合的关系 对于氯噻嗪和头孢尼西，将使用方程进行评估 它们表示实验上可分离的模型和它们的 固有的假设。这些关系的确切性质 将允许人们确定是否以及在多大程度上， 这两种化合物的肾提取仅限于 免费药品循环使用。有和没有的实验 血管紧张素II应有助于阐明敏感程度 和血流诱导的肾脏排泄变化的机制 速尿、氯噻嗪和头孢尼西。这些研究将 洞察肾脏个体差异的影响 转运活性、药代动力学相互作用与疾病 关于肾脏药物消除的州。在这样做的时候，更理性 将为这些项目的事先剂量调整提供指导方针 肾脏排泄对变化敏感的治疗药物 在蛋白质结合或肾脏血流方面。

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.