Abstract：
Equilibrium dialysis (ED) is widely used in pharmacokinetics to determine the fraction of unbound (fu) compounds in plasma; however, the kinetics of drugs in the ED system with respect to their permeation across semi-permeable membranes has not been systemically studied. Here, the kinetics of the ED system, including the binding of drugs to plasma proteins, non-specific binding, and permeation across the membrane, was described to enable verification of the equilibrium, prediction of the time to reach equilibrium, and estimations of fu with data obtained during pre-equilibrium. Using data obtained during pre-equilibrium, the time to reach 90% equilibrium (t90%) and fu were estimated with reasonable accuracy. Notably, fu could be estimated reasonably well using one-time-point data for the calculation. Furthermore, the current modeling approach allowed concurrent estimations of fu and the decomposition rate of compounds that were metabolically unstable in the plasma. Reasonable metabolic rate constants were determined for cefadroxil and diltiazem, demonstrating the practicality of this method for determining kinetics related to fu characterization. Because the determination of fu of compounds with \'unfavorable\' physicochemical properties is known to be experimentally challenging, the current method may be useful in determining the fu of compounds in vitro.
摘要：
平衡透析（ED）广泛用于药代动力学，以确定血浆中未结合（fu）化合物的分数；但是，药物在ED系统中通过半透膜渗透的动力学尚未得到系统研究。这里,ED系统的动力学，包括药物与血浆蛋白的结合，非特异性结合，和渗透穿过膜，被描述为能够验证平衡，预测达到平衡的时间，以及用平衡前获得的数据估计fu。使用在预平衡期间获得的数据，达到90％平衡的时间（t90％）和fu进行了合理的估计。值得注意的是,使用一个时间点的数据进行计算，可以很好地估计fu。此外，目前的建模方法允许同时估计fu和血浆中代谢不稳定化合物的分解速率.确定头孢羟氨苄和地尔硫卓的合理代谢率常数，证明了该方法用于确定与fu表征相关的动力学的实用性。由于已知具有“不利”物理化学性质的化合物的fu的测定在实验上具有挑战性，该方法可用于体外测定化合物的fu。
