Department of Pharmacy Practice, Purdue University, Indianapolis, IN, 46202, United States.
Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Clinical Pharmacology Analytical Core, Indianapolis, IN, 46202, United States.
J Pharm Biomed Anal. 2021 Feb 20;195:113872. doi: 10.1016/j.jpba.2020.113872. Epub 2020 Dec 26.
Pharmacologic effects elicited by drugs most directly relate to their unbound concentrations. Measurement of binding in blood, plasma and target tissues are used to estimate these concentrations by determining the fraction of total concentration in a biological matrix that is not bound. In the case of attempting to estimate R- and S-bupropion concentrations in plasma and brain following racemic bupropion administration, reversible chiral inversion and irreversible degradation of the enantiomers were hypothesized to confound attempts at unbound fraction estimation. To address this possibility, a kinetic modeling approach was used to quantify inversion and degradation specific processes for each enantiomer from separate incubations of each enantiomer in the two matrices, and in pH 7.4 buffer, which is also used in binding experiments based on equilibrium dialysis. Modeling analyses indicated that chiral inversion kinetics were two to four-fold faster in plasma and brain than degradation, with only inversion observed in buffer. Inversion rate was faster for S-bupropion in the three media; whereas, degradation rates were similar for the two enantiomers in plasma and brain, with overall degradation in plasma approximately 2-fold higher than in brain homogenate. Incorporation of degradation and chiral inversion kinetic terms into a model to predict enantiomer-specific binding in plasma and brain revealed that, despite existence of these two processes, empirically derived estimates of fraction unbound were similar to model-derived values, leading to a firm conclusion that observed extent of plasma and brain binding are accurate largely because binding kinetics are faster than parallel degradation and chiral inversion processes.
药物引起的药理作用与其游离浓度最直接相关。通过测定生物基质中总浓度中非结合部分的分数，测量血液、血浆和靶组织中的结合情况，用于估计这些浓度。在尝试估算外消旋布比卡因给药后血浆和脑中 R-和 S-布比卡因浓度的情况下，假设对映体的可逆手性反转和不可逆降解会干扰非结合分数的估算。为了解决这个问题，采用了一种动力学建模方法，从每个对映体在两个基质中的单独孵育以及在 pH 7.4 缓冲液中（也用于基于平衡透析的结合实验），定量估计每个对映体的反转和降解特定过程。模型分析表明，手性反转动力学在血浆和脑中比降解快两到四倍，仅在缓冲液中观察到反转。在手性反转的三个介质中，S-布比卡因的速度更快；然而，在血浆和脑中，两个对映体的降解速率相似，血浆中的总体降解速率约为脑匀浆的两倍。将降解和手性反转动力学项纳入预测血浆和脑中对映体特异性结合的模型中，结果表明，尽管存在这两个过程，但经验衍生的非结合分数估计值与模型衍生值相似，从而得出一个坚定的结论，即观察到的血浆和脑结合程度是准确的，主要是因为结合动力学比平行降解和手性反转过程更快。
