How well do Lipophilicity Parameters, MEEKC Microemulsion Capacity Factor, and Plasma Protein Binding Predict CNS Tissue Binding?
How well do Lipophilicity Parameters, MEEKC Microemulsion Capacity Factor, and Plasma Protein Binding Predict CNS Tissue Binding?
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DOI：
10.1002/jps.23081
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发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Molina-Martin, Manuel
中科院分区：
文献类型：
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作者：
Zamek-Gliszczynski, Maciej J.;Sprague, Karen E.;Molina-Martin, Manuel
脑游离分数（Fu）是了解中枢神经系统（CNS）药物药代动力学的关键，因此已提出了几个替代预测。目前，脑Fu，微乳液电动色谱容量因子（MEEKC k '），血浆Fu，辛醇-水分配系数（clogP），并在pH 7.4的LogP（clogD（7.4））之间的相关性进行了比较，为94个不同的分子，另外为587种化合物。MEEKC k'对脑Fu的预测作用（r（2）= 0.74）优于计算的亲脂性参数（clogP r（2）= 0.51-0.54，clogD（7.4）r（2）= 0.41-0.44），但不上级血浆Fu（r（2）= 0.74-0.85）。MEEKC k'不能预测血浆Fu（r（2）= 0.58）和脑Fu，与clogP或clogD（7.4）相比改善程度（r（2）= 0.41-0.49）不太明显。尽管双对数相关分析支持MEEKC k'和血浆Fu对脑Fu的强预测（r（2）>= 0.74），但预测误差分析估计，使用MEEKC k'和血浆Fu估计的脑Fu的预测区间分别为10倍和6.9-8.6倍。因此，MEEKC k'和血浆Fu可以预测CNS组织结合的对数级，但它们不能提供支持体外至体内外推和药代动力学/动态数据解释所需的真正定量的脑Fu预测。(C)2012 Wiley Periodicals，Inc.和美国药学协会药物科学杂志101：1932-1940，2012
Brain fraction unbound (Fu) is critical to understanding the pharmacokinetics/ dynamics of central nervous system (CNS) drugs, thus several surrogate predictors have been proposed. At present, correlations between brain Fu, microemulsion electrokinetic chromatography capacity factor (MEEKC k'), plasma Fu, octanol-water partition coefficient (clogP), and LogP at pH 7.4 (clogD(7.4)) were compared for 94 diverse molecules, and additionally for 587 compounds. MEEKC k' was a better predictor of brain Fu (r(2) = 0.74) than calculated lipophilicity parameters (clogP r(2) = 0.51-0.54, clogD(7.4) r(2) = 0.41-0.44), but it was not superior to plasma Fu (r(2) = 0.74-0.85) as a predictor of brain Fu. MEEKC k' did not predict plasma Fu(r(2) = 0.58) as well as brain Fu, and the extent of improvement over clogP or clogD(7.4) (r(2) = 0.41-0.49) was less pronounced. Although log-log-correlation analysis supported seemingly strong prediction of brain Fu both by MEEKC k' and by plasma Fu (r(2) >= 0.74), analysis of prediction error estimated a 10-fold and 6.9-8.6-fold prediction interval for brain Fu estimated using MEEKC k' and plasma Fu, respectively. Therefore, MEEKC k' and plasma Fu can predict the log order of CNS tissue binding, but they cannot provide truly quantitative brain Fu predictions necessary to support in-vitro-to-in-vivo extrapolations and pharmacokinetic/dynamic data interpretation. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:1932-1940, 2012