Showa Pharmaceutical University.
Tokyo office, Nara Institute of Science and Technology.
J Toxicol Sci. 2024;49(4):127-137. doi: 10.2131/jts.49.127.
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.
辛醇/水分配系数 P（logP）是一种疏水性指数，是口服给药物质药代动力学的决定因素之一，因为它会影响膜通透性。为了说明化学空间中化合物的广泛多样性，先前基于物质的计算化学描述符提出了一个由 25 个块组成的二维数据图。大约 200 种不同化学物质的 logP 值（包括覆盖化学空间所有 25 个块的测试和参考化合物）通过反相液相色谱中的保留时间进行实验估算；这些值与具有既定 logP 值的真实参考化合物（在经济合作与发展组织测试指南 117 中可用的 60 种参考物质中的 17 种）进行了比较。使用四种不同的流动相条件（pH 值为 2、4、7 和 10 的分子形式）成功估算了 165 种化学物质中的 140 种 logP 值，与使用 ChemDraw 和 ACD/Percepta 计算的 logP 值显著相关（r > 0.72）。尽管在化学空间中与真实化合物相邻的物质的实验和计算估算的 logP 值具有精确相关性，但一些与真实物质相隔较远的物质的 logP 值低于计算值。这些结果表明，应在国际测试指南中包含具有更广泛化学多样性的额外真实参考物质及其反相液相色谱中的 logP 值，以促进对辛醇/水分配系数的简单可靠估算，这是一般化学物质药代动力学的重要决定因素。
