Impact of pH on plasma protein binding in equilibrium dialysis
Impact of pH on plasma protein binding in equilibrium dialysis
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DOI：
10.1021/mp800004s
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发表时间：
2008-05-01
影响因子：
4.9
通讯作者：
Korzekwa, Kenneth R.
中科院分区：
文献类型：
--
作者：
Kochansky, Christopher J.;McMasters, Daniel R.;Korzekwa, Kenneth R.
许多药代动力学分析需要非结合血浆浓度，包括预测清除率、分布体积、药物-药物相互作用、脑摄取分析等。测量药物总量通常更为方便。血浆中的浓度，而不是未结合的药物浓度。为了获得未结合的血浆浓度，通常在血清或血浆中对药物的血浆蛋白结合进行单独的体外测定，然后通过该未结合分数（f(u,p)）对血浆药代动力学结果进行数学调整。已知血浆蛋白结合或血浆中未结合的药物部分（f(u,p)）受血浆样品中蛋白质、药物、游离脂肪酸浓度、脂蛋白分配、温度、pH和其他药物/替代剂的存在与否的影响。由于缺乏足够的pH控制，在血浆蛋白结合的新检测格式（例如，96孔平衡薄壁聚丙烯透析板）中，f（u,p）测定的误差将对这些药代动力学计算产生重大的药物特异性影响。使用55种不同的药物和96孔平衡透析板格式，在平衡透析实验中，不同的pH值对f（u,p）测量值的影响进行了检查。人血浆与Dulbecco磷酸盐缓冲盐水在空气或10% CO2气氛下，在37℃下平衡透析22小时，最终pH分别约为8.7和7.4。在pH 7.4 （10% CO2）与pH 8.7（空气）条件下，f（u,p）的比值为>= 2.0。在测试的55种化合物中，只有一种具有比率
Many pharmacokinetic analyses require unbound plasma concentrations, including prediction of clearance, volume of distribution, drug-drug interactions, brain uptake analysis, etc. It is most often more convenient to measure the total drug. concentration in plasma rather than the,unbound drug concentration. To arrive at unbound plasma concentrations, separate in vitro determinations of the plasma protein binding of a drug are usually carded out in serum or in plasma, and the plasma pharmacokinetic results are then mathematically adjusted by this fraction unbound (f(u,p)). Plasma protein binding or the drug fraction unbound in plasma (f(u,p)) is known to be affected by protein, drug, free fatty acid concentrations, lipoprotein partitioning, temperature, pH, and the presence or absence of other drugs/ displacing agents within plasma samples. Errors in f(u,p) determination caused by lack of adequate pH control in newer assay formats for plasma protein binding (e.g., 96-well equilibrium thin walled polypropylene dialysis plates) will have significant drug-specific impact on these pharmacokinetic calculations. Using a diverse set of 55 drugs and a 96-well equilibrium dialysis plate format, the effect of variable pH during equilibrium dialysis experiments on measured values of f(u,p) was examined. Equilibrium dialysis of human plasma against Dulbecco's phosphate buffered saline at 37 degrees C under an air or 10% CO2 atmosphere for 22 h resulted in a final pH of approximately 8.7 and 7.4, respectively. The ratio of f(u,p) at pH 7.4 (10% CO2) VS pH 8.7 (air) was >= 2.0 for 40% of the 55 compounds tested. Only one of the 55 compounds tested had a ratio