Estimating the fraction absorbed (F_abs) of orally ingested chemicals in the human gastrointestinal tract is pivotal for assessing chemical concentrations in the systemic circulation and informing potential toxicological impacts, especially in the era of “new approach methods” targeting chemical screening and prioritization. Here, we present an input-parsimonious and computationally efficient approach to support the screening-level estimation of F_abs from partitioning (characterized using the octanol–water partition coefficient at pH 7.4, K_OW) and transmembrane permeability (characterized using the Caco-2 apparent permeability, P_app,Caco-2), based on a mechanistic description of processes involved in chemical absorption:$F_{\mathrm{a}\mathrm{b}\mathrm{s}}=1-e^{\frac{-16457}{\left[\left(1-2.40\times {10}^{-9}\right)+2.40\times {10}^{-9}\bullet K_{\mathrm{O}\mathrm{W}}\right]\bullet \left[\frac{1}{0.0075}\bullet {\left(\frac{1}{P_{\mathrm{a}\mathrm{p}\mathrm{p},\mathrm{C}\mathrm{a}\mathrm{c}\mathrm{o}-2}}-\frac{1}{0.00153}\right)}^{0.346}+\frac{1}{0.00115}\right]}}$$F_{\mathrm{a}\mathrm{b}\mathrm{s}}=1-e^{\frac{-16457}{\left[\left(1-2.40\times {10}^{-9}\right)+2.40\times {10}^{-9}\bullet K_{\mathrm{O}\mathrm{W}}\right]\bullet \left[\frac{1}{0.0075}\bullet {\left(\frac{1}{P_{\mathrm{a}\mathrm{p}\mathrm{p},\mathrm{C}\mathrm{a}\mathrm{c}\mathrm{o}-2}}-\frac{1}{0.00153}\right)}^{0.346}+\frac{1}{0.00115}\right]}}$Our approach demonstrates satisfactory performance in predicting F_abs for 176 hydrophobic and hydrophilic organic chemicals, with a Pearson correlation coefficient greater than 0.75 and a root mean square error of approximately 15 % in absolute F_abs values between experimental measurements and predictions. Our results show that the F_abs of highly hydrophobic chemicals (K_OW > 10⁸) are closely dependent on partitioning, whereas the F_abs of relatively hydrophilic chemicals (K_OW < 10⁶) are sensitive to transmembrane permeability. We also demonstrate that transmembrane permeability and partitioning are not interdependent, and both should be treated as fundamental chemical properties in predicting F_abs.

中文翻译：

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阐明分区和跨膜通透性对人体胃肠道化学物质吸收的影响


估计人体胃肠道中口服摄入的化学物质的吸收分数 （F_abs） 对于评估体循环中的化学物质浓度和告知潜在的毒理学影响至关重要，尤其是在针对化学筛选和优先排序的“新方法”时代。在这里，我们提出了一种输入简洁且计算高效的方法，以支持从分配（使用 pH 7.4 下的辛醇-水分配系数，K_OW 表征）和跨膜通透性（使用 Caco-2 表观渗透率，P_app，Caco-2 表征）的筛选水平估计，基于涉及化学吸收过程的机械描述：$F_{\mathrm{a}\mathrm{b}\mathrm{s}}=\mathrm{}{}^{\frac{\mathrm{1-e-16457}}{\left[\left(\mathrm{}\mathrm{1-2.40}\times {\mathrm{10-9}}^{\mathrm{}}\right)+2.40\times {\mathrm{10-9}}^{\mathrm{}}\bullet K_{\mathrm{O}\mathrm{W}}\right]\bullet \left[\frac{1}{0.0075}\bullet {\left(\frac{1}{P_{\mathrm{a}\mathrm{p}\mathrm{}p，C\mathrm{}\mathrm{a}\mathrm{c}\mathrm{}o-2-1\mathrm{}}}\frac{\mathrm{}}{0.00153}\right)}^{0.346}+\frac{1}{0.00115}\right]}}$我们的方法在预测 176 种疏水和亲水性有机化学品的 F_abs 方面表现出令人满意的性能，皮尔逊相关系数大于 0。75 和实验测量和预测之间的绝对 F_abs 值的均方根误差约为 15%。我们的结果表明，高疏水性化学品 （K_OW > 10⁸） 的 F_abs 密切相关于分配，而相对亲水性化学品 （K_OW < 10⁶） 的 F_abs 对跨膜通透性敏感。我们还证明跨膜通透性和分配不是相互依赖的，两者都应被视为预测 F_abs 的基本化学性质。