Decision trees to characterise the roles of permeability and solubility on the prediction of oral absorption
Decision trees to characterise the roles of permeability and solubility on the prediction of oral absorption
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DOI：
10.1016/j.ejmech.2014.12.006
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发表时间：
2015-01-27
影响因子：
6.7
通讯作者：
Ghafourian, Taravat
中科院分区：
文献类型：
--
作者：
Newby, Danielle;Freitas, Alex A.;Ghafourian, Taravat
化合物的口服吸收取决于许多生理、理化和制剂因素。控制口服吸收的两个重要特性是体外渗透性和溶解度，它们通常用作人体肠道吸收的指标。尽管如此，这些参数之间关系的本质和确切特征尚不清楚。在这项研究中，对人类肠道吸收的大量数据集以及相同化合物的体外渗透性、水溶性、熔点和最大剂量进行了整理。该数据集允许客观地建立渗透性阈值来预测肠道吸收的高或低。使用该渗透性阈值，开发并验证了包含溶解度相关参数（例如实验或预测溶解度或基于熔点的吸收势（MPbAP））以及结构分子描述符的分类决策树，以预测口服吸收类别。决策树能够确定渗透性和溶解度在口服吸收过程中的各自作用。具有高溶解度的低渗透性化合物表现出低肠道吸收，而具有高或低渗透性的水溶性差的化合物可能具有高肠道吸收，只要它们具有某些分子特征，例如小的极性表面或特定的拓扑结构。 (C) 2015 Elsevier Masson SAS。版权所有。
Oral absorption of compounds depends on many physiological, physiochemical and formulation factors. Two important properties that govern oral absorption are in vitro permeability and solubility, which are commonly used as indicators of human intestinal absorption. Despite this, the nature and exact characteristics of the relationship between these parameters are not well understood. In this study a large dataset of human intestinal absorption was collated along with in vitro permeability, aqueous solubility, melting point, and maximum dose for the same compounds. The dataset allowed a permeability threshold to be established objectively to predict high or low intestinal absorption. Using this permeability threshold, classification decision trees incorporating a solubility-related parameter such as experimental or predicted solubility, or the melting point based absorption potential (MPbAP), along with structural molecular descriptors were developed and validated to predict oral absorption class. The decision trees were able to determine the individual roles of permeability and solubility in oral absorption process. Poorly permeable compounds with high solubility show low intestinal absorption, whereas poorly water soluble compounds with high or low permeability may have high intestinal absorption provided that they have certain molecular characteristics such as a small polar surface or specific topology. (C) 2015 Elsevier Masson SAS. All rights reserved.