Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values
Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values
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DOI：
10.1016/j.xphs.2018.07.017
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发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Dahan, Arik
中科院分区：
文献类型：
--
作者：
Wolk, Omri;Markovic, Milica;Dahan, Arik
这项工作的目标是开发一种计算机模型，允许预测整个小肠(SI)的节段性通透性。对11种模型药物在3个SI段(空肠、中段SI、回肠)的体内渗透性进行了研究，建立了一个反映整个SI情况的数据集。然后，开发了一个预测模型，将影响被动渗透性的基本机制的物理化学药物特性：对数p、极表面积、M-W、H-键数和对数f(U)与微环境SI条件相结合。预测数据和实验数据之间有很好的相关性(R-2=0.914)，在每个SI节段具有相似的可预测性。Log p和Log f(U)被确定为渗透率的主要决定因素，其贡献相似。氢键总数也是一个重要的决定因素，其次是极表面积和M-W。省略任何模型参数都会降低其可预测性。该模型以5种外用药物进行了验证，具有很好的预测性。值得注意的是，该模型能够预测实验上显示这一趋势的所有药物的节段依赖的渗透性。在高渗透率与低渗透率范围内，模型的预测性较好。总体而言，我们构建了一个简单的In Silico模型，可以可靠地预测节段性依赖的肠道通透性，为药物相关因素和胃肠道环境对通透性的相对影响提供了新的见解。(C)2019年美国药剂师协会(R)。爱思唯尔公司出版，版权所有。
The goal of this work was to develop an in silico model that allows predicting segmental-dependent permeability throughout the small intestine (SI). In vivo permeability of 11 model drugs in 3 SI segments (jejunum, mid-SI, ileum) was studied in rats, creating a data set that reflects the conditions throughout the SI. Then, a predictive model was developed, combining physicochemical drug properties influencing the underlying mechanism of passive permeability: Log p, polar surface area, M-W, H-bond count, and Log f(u), with microenvironmental SI conditions. Excellent correlation was evident between the predicted and experimental data (R-2 = 0.914), with similar predictability in each SI segment. Log p and Log f(u) were identified as the major determinants of permeability, with similar contribution. Total H-bond count was also a significant determinant, followed by polar surface area and M-W. Leaving out any of the model parameters decreased its predictability. The model was validated against 5 external drugs, with excellent predictability. Notably, the model was able to predict the segmental-dependent permeability of all drugs showing this trend experimentally. Model predictability was better in the high-permeability versus low-permeability range. Overall, our approach of constructing a straightforward in silico model allowed reliable predictions of segmental-dependent intestinal permeability, providing new insights into relative effects of drug-related factors and gastrointestinal environment on permeability. (C) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.