Troconiz I F, Lopez-Bustamante L G, Fos D
Department of Pharmacology, School of Medicine, University of Basque Country, Leioa, Spain.
J Pharm Sci. 1995 Dec;84(12):1482-7. doi: 10.1002/jps.2600841216.
This study was designed to establish the in vivo relationship between tenoxicam disposition and changes in plasma protein binding measured as an unbound fraction in plasma (fu). Tenoxicam was administered as a bolus 5-mg/kg dose, and total plasma concentrations, plasma albumin percentage, and fu were examined in five groups of rats (uremia or anephric states were experimentally induced in four groups to decrease plasma protein levels). Albumin levels were significantly decreased in all experimentally altered groups with respect to control animals (p < 0.01). A two-compartment population pharmacokinetic model that includes the effect of fu on the kinetic parameters was proposed to describe tenoxicam plasma concentration profiles. Plasma clearance (CL) increased but not proportionally with fu. Apparent volume of distribution of the central compartment (V) was linearly related to changes in fu and intercompartmental clearance was not affected by altered plasma protein binding. Expressing pharmacokinetic parameters as a function of fu resulted in a three- and five-fold decrease in the variability associated with CL and V, respectively.
本研究旨在建立替诺昔康处置与血浆蛋白结合变化之间的体内关系，血浆蛋白结合变化以血浆中未结合分数（fu）来衡量。以5mg/kg的剂量推注给予替诺昔康，并在五组大鼠中检测总血浆浓度、血浆白蛋白百分比和fu（在四组中通过实验诱导尿毒症或无肾状态以降低血浆蛋白水平）。与对照动物相比，所有实验改变组的白蛋白水平均显著降低（p<0.01）。提出了一个二室群体药代动力学模型，该模型包括fu对动力学参数的影响，以描述替诺昔康的血浆浓度曲线。血浆清除率（CL）增加，但与fu不成比例。中央室的表观分布容积（V）与fu的变化呈线性关系，而室间清除率不受血浆蛋白结合改变的影响。将药代动力学参数表示为fu的函数，分别使与CL和V相关的变异性降低了三到五倍。
