McNamara P J, Gibaldi M, Stoeckel K
Eur J Clin Pharmacol. 1983;25(3):407-12. doi: 10.1007/BF01037956.
Guidelines presented previously for the analysis of plasma concentration versus time data for a drug exhibiting concentration-dependent plasma protein binding were successfully applied to the distributional parameters of a new cephalosporin, ceftriaxone. This approach provided several striking observations when the pharmacokinetics of ceftriaxone in a healthy and uremic population were re-examined. First, the parameter -fp converted the apparent dose-dependent distributional terms of ceftriaxone into a function of the concentration-dependent plasma protein binding. Second, a strong correlation between the term VUSS and the reciprocal of -fp was established within each of the two populations. While this -fp term accounted for the variability within the respective populations due to ceftriaxone-albumin binding differences, it did not account for all of the distributional differences between the two populations. The present analysis revealed that the altered physiologic state of uremia (larger plasma volumes and interstitial to intravascular albumin ratios), in addition to differences in plasma protein binding, dictated the distribution of ceftriaxone in healthy and uremic subjects. Furthermore, the binding-disposition model which accounts for the presence of plasma proteins outside the vascular space, was established to be appropriate in describing the distribution of ceftriaxone.
先前提出的用于分析具有浓度依赖性血浆蛋白结合的药物的血浆浓度与时间数据的指导原则，已成功应用于一种新型头孢菌素——头孢曲松的分布参数。当重新审视头孢曲松在健康人群和尿毒症人群中的药代动力学时，这种方法提供了几个显著的观察结果。首先，参数-fp将头孢曲松明显的剂量依赖性分布项转化为浓度依赖性血浆蛋白结合的函数。其次，在两个人群中的每一个人群中，VUSS项与-fp的倒数之间都建立了很强的相关性。虽然这个-fp项解释了由于头孢曲松与白蛋白结合差异导致的各人群内部的变异性，但它并没有解释两个人群之间所有的分布差异。目前的分析表明，除了血浆蛋白结合的差异外，尿毒症改变的生理状态（更大的血浆容量和组织间液与血管内白蛋白的比例）决定了头孢曲松在健康和尿毒症受试者中的分布。此外，考虑到血管外血浆蛋白存在的结合-处置模型被确定适用于描述头孢曲松的分布。
