PROTEIN BINDING/ORGAN PERFUSION AND RENAL DRUG TRANSPORT

数学描述与 肾脏药物清除的生物学决定因素尚不清楚 定义或充分验证。 特别是， 蛋白结合和肾血流量对分泌转运的影响 药物仍然被认为是描述性的，而不是定量的 方式 因此，建议的主要目标 研究的目的是：1）更好地了解蛋白质的作用 结合两种模型化合物的肾转运动力学 （氯噻嗪和头孢尼西），2）以确定是否率 肾小管分泌的上述功能是一个功能的自由 或总血浆浓度，和3）研究，在定量 以这种方式，器官灌注的变化对肾脏和 三种模型化合物（呋塞米， 氯噻嗪和头孢尼西）。 将使用隔离的灌注大鼠进行药物研究 肾脏制备。 牛血清的各种组合 将使用白蛋白和葡聚糖以产生广泛的 蛋白质结合研究的价值。 血管紧张素Ⅱ a 传入和传出强缩血管激素 肾脏中的小动脉将用于改变肾脏灌注液流量 在器官灌注研究中。 呋塞米，氯噻嗪，和 头孢尼西的含量测定采用HPLC法，菊粉的含量测定采用液相色谱法 计数，比色法测定葡萄糖，火焰法测定钠 测光法 灌注液中药物的蛋白结合将是 使用平衡透析技术测定。 肾脏药物排泄与蛋白结合的关系 将使用以下公式评价氯噻嗪和头孢尼西 它们代表了实验上可分离的模型， 固有的假设。 这些关系的确切性质 将使人们能够确定是否，以及在多大程度上， 这两种化合物的肾提取仅限于 再循环游离药物。 实验有和没有 血管紧张素II应该有助于阐明 和机制的流量引起的变化，在肾脏排泄的 呋塞米氯噻嗪和头孢尼西。 这些研究将 提供了对肾脏疾病个体差异的影响的深入了解， 转运活性、药代动力学相互作用和疾病 国家对肾脏药物消除。 这样做，更理性 将提供指导原则，以调整这些药物的剂量。 肾排泄对变化敏感的治疗剂 蛋白质结合或肾血流量。

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.