Abstract：
The octanol/water partition coefficient P (logP) is a hydrophobicity index and is one of the determining factors for the pharmacokinetics of orally administered substances because it influences membrane permeability. To illustrate the wide-ranging variety of compounds in the chemical space, a two-dimensional data plot consisting of 25 blocks was previously proposed based on a substance\'s in silico chemical descriptors. The logP values of approximately 200 diverse chemicals (test plus reference compounds covering all 25 blocks of the chemical space) were estimated experimentally using retention times in reverse-phase liquid chromatography; these values were compared with those of authentic reference compounds with established logP values (available for 17 of 60 reference substances in the Organization for Economic Co-operation and Development Test Guideline 117). The logP values of 140 of 165 chemicals successfully estimated using four different mobile phase conditions (pH 2, 4, 7, and 10 for molecular forms) correlated significantly with those calculated using the in silico packages ChemDraw and ACD/Percepta (r > 0.72). Although substances that neighbored authentic compounds in the chemical space had precisely correlated logP values estimated experimentally and in silico, some compounds that were more distant from authentic substances showed lower logP values than those estimated in silico. These results indicate that additional authentic reference materials with wider ranging chemical diversity and their logP values from reverse-phase liquid chromatography should be included in the international test guidance to promote simple and reliable estimation of octanol/water partition coefficients, which are important determinant factors for the pharmacokinetics of general chemicals.
摘要：
辛醇/水分配系数P(logP)是疏水性指数,并且是口服给药物质的药代动力学的决定因素之一,因为它影响膜通透性。为了说明化学领域中各种各样的化合物，一个由25块组成的二维数据图以前是基于一种物质的计算机化学描述符提出的。使用反相液相色谱中的保留时间，通过实验估算了大约200种不同化学物质（涵盖化学空间的所有25个区块的测试和参考化合物）的logP值；将这些值与具有已确定logP值的真实参考化合物的值进行了比较（可用于经济合作与发展组织测试指南117中的60种参考物质中的17种）。使用四种不同的流动相条件（分子形式的pH为2、4、7和10）成功估计的165种化学物质中的140种的logP值与使用计算机模拟包装ChemDraw和ACD/Percepta计算的logP值显着相关（r>0.72）。尽管在化学空间中与真实化合物相邻的物质具有通过实验和计算机模拟估算的精确相关的logP值，一些与真实物质相距较远的化合物的logP值低于计算机估算的logP值.这些结果表明，具有更广泛的化学多样性的其他真实参考材料及其来自反相液相色谱的logP值应该包括在国际测试指南中，以促进辛醇/水分配系数的简单可靠估计。这是一般化学品药代动力学的重要决定因素。
