Investigation of the retention behavior of structurally diverse drugs on alpha1 acid glycoprotein column: Insight on the molecular factors involved and correlation with protein binding data
Investigation of the retention behavior of structurally diverse drugs on alpha1 acid glycoprotein column: Insight on the molecular factors involved and correlation with protein binding data
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DOI：
10.1016/j.ejps.2014.04.015
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发表时间：
2014-08-18
影响因子：
4.6
通讯作者：
Tsantili-Kakoulidou, Anna
中科院分区：
文献类型：
--
作者：
Chrysanthakopoulos, Marios;Vallianatou, Theodosia;Tsantili-Kakoulidou, Anna
研究了49种结构不同的药物在不同层析条件下在α(1)酸性糖蛋白柱上的保留情况。采用不同比例的乙腈和异丙醇作为有机改性剂，用PBS调节pH值至7.0。亲油性和静电相互作用的外推保留率和等度保留率的分析表明，有机改性剂的性质和比例对固定相有显著影响，这归因于缓冲成分对固定相带电中心的屏蔽程度不同。AGP保留因子与先前分析的HSA保留因子进行了比较。LSER分析的应用表明，氢键酸度、偶极/极化率和过量摩尔折射率是所有AGP层析指数的最重要参数，阐明了AGP保留与辛醇-水分配和HSA保留的区别。一项试图将AGP层析指数与AGP结合常数相关联的尝试，支持了固定屏蔽在保留机制中的重要性。因此，等度保留因子logk(10(ACN))(AGP)在A变体的情况下表现出中等但仍然比亲脂性更好的性能，并且可能是一个有用的工具。用于相关缔合常数的估计。对于F1/S结合模拟，需要较低的固定相屏蔽才能获得显著的二项回归方程，其中logk(20(Acn))(Agp)的贡献仅次于以分子量表示的最重要的体积效应。(C)2014爱思唯尔B.V.保留所有权利。
Retention of 49 structurally diverse drugs on alpha(1) acid glycoprotein column was investigated under different chromatographic conditions. Acetonitrile and 2-propanol were used as organic modifiers at different percentages and the pH was adjusted at 7.0 using PBS. Analysis of extrapolated and isocratic retention in terms of lipophilicity and electrostatic interactions revealed significant effect of the nature and percentage of organic modifier, which was attributed to the different shielding degree of the charged sites on the stationary phase by the buffer constituents. AGP retention factors were compared to HSA retention factors analyzed previously. Application of LSER analysis, extended to incorporate fractions ionized, demonstrated hydrogen bond acidity, dipolarity/polarizability and excess molar refraction as the most significant parameters for all AGP chromatographic indices, elucidating the differentiation of AGP retention from octanol-water partitioning and HSA retention. An attempt to correlate AGP chromatographic indices to AGP association constants, available in literature, supported the importance of stationary shielding in retention mechanism. Thus, isocratic retention factors log k(10(ACN))(AGP) show a moderate but still better performance than lipophilicity in the case of A variant and may be a useful tool. for the estimation of relevant association constants. For F1/S binding simulation lower stationary phase shielding is needed to obtain a significant two term regression equation, where log k(20(ACN))(AGP) exerts a secondary contribution next to the most important bulk effect expressed by molecular weight. (C) 2014 Elsevier B.V. All rights reserved.