Yacobi A, Lai C M, Levy G
J Pharm Sci. 1977 Dec;66(12):1741-3. doi: 10.1002/jps.2600661222.
The purpose of this investigation was to determine, with respect to dicumarol, the effect of plasma protein binding on the pharmacokinetic parameters used conventionally to describe the distribution kinetics of a drug on the basis of the time course of its plasma concentration. After rapid intravenous injection, plasma dicumarol concentrations in adult male Sprague-Dawley rats declined triexponentially, with the terminal exponential phase starting at about 4 hr. The free fraction f, of dicumarol in the serum of individual animals ranged from 0.000150 to 0.000790. The parameters of the equation Ct = Pe-pit + Ae-alphat + Be-betat for plasma concentration Ct at time t were obtained by nonlinear least-squares computer fitting of the experimental data and varied appreciably between animals. Of these parameters, only beta showed a significant correlation with f. These observations indicate that the distribution kinetics of this very extensively plasma protein-bound drug, as reflected by the time course of its plasma concentration after intravenous injection, are apparently not affected by intersubject differences in plasma protein binding. There is a remarkable similarity in the valves of P, A, B, pi, and alpha for dicumarol and warfarin, even though the serum free fraction of these drugs differs considerably.
本研究的目的是确定，就双香豆素而言，血浆蛋白结合对基于血浆浓度随时间变化过程来描述药物分布动力学的常规药代动力学参数的影响。在成年雄性斯普拉格 - 道利大鼠快速静脉注射后，血浆双香豆素浓度呈三指数下降，终末指数相大约在4小时开始。个体动物血清中双香豆素的游离分数f在0.000150至0.000790之间。通过对实验数据进行非线性最小二乘计算机拟合，得到时间t时血浆浓度Ct的方程Ct = Pe - pit + Ae - alphat + Be - betat的参数，这些参数在动物之间有明显变化。在这些参数中，只有β与f呈显著相关。这些观察结果表明，这种与血浆蛋白高度结合的药物的分布动力学，如静脉注射后其血浆浓度随时间的变化过程所反映的，显然不受个体间血浆蛋白结合差异的影响。双香豆素和华法林在P、A、B、pi和α值上有显著相似性，尽管这些药物的血清游离分数有很大差异。
