Quantitative prediction of pharmacokinetic properties of drugs in humans: Recent advance in in vitro models to predict the impact of efflux transporters in the small intestine and blood brain barrier
Quantitative prediction of pharmacokinetic properties of drugs in humans: Recent advance in in vitro models to predict the impact of efflux transporters in the small intestine and blood brain barrier
复制标题
人体药物药代动力学特性的定量预测：预测外排转运蛋白对小肠和血脑屏障影响的体外模型的最新进展
DOI：
10.1016/j.jphs.2021.10.010
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发表时间：
2022
影响因子：
3.5
通讯作者：
Kusuhara Hiroyuki
中科院分区：
文献类型：
--
作者：
Hashimoto Yoshiki;Michiba Kazuyoshi;Maeda Kazuya;Kusuhara Hiroyuki
外排转运系统对于抑制外源性物质从肠腔的吸收和保护血组织屏障（例如血脑屏障）处的关键组织是必不可少的。药物外排转运的功能是由多种转运蛋白所主导的。大量的临床证据表明，转运蛋白的遗传变异与联合用药会影响转运蛋白的表达和/或功能，进而影响底物药物的药代动力学。因此，在药物开发的临床前阶段，已经使用各种体外实验工具定量预测了外排转运蛋白以及摄取转运蛋白和代谢酶对人体药物药代动力学的影响。各种人源性细胞系统可用于精确预测药物在人体内的转运。由每个内在代谢或运输过程组成的数学建模使我们能够通过将各种实验结果整合到模型参数中来了解药物在器官水平和全身水平的处置。本文综述了外排转运蛋白在药物肠吸收和脑分布中的作用，以及预测工具和方法的最新进展。
Efflux transport systems are essential to suppress the absorption of xenobiotics from the intestinal lumen and protect the critical tissues at the blood-tissue barriers, such as the blood–brain barrier. The function of drug efflux transport is dominated by various transporters. Accumulated clinical evidences have revealed that genetic variations of the transporters, together with coadministered drugs, affect the expression and/or function of transporters and subsequently the pharmacokinetics of substrate drugs. Thus, in the preclinical stage of drug development, quantitative prediction of the impact of efflux transporters as well as that of uptake transporters and metabolic enzymes on the pharmacokinetics of drugs in humans has been performed using variousin vitroexperimental tools. Various kinds of human-derived cell systems can be applied to the precise prediction of drug transport in humans. Mathematical modeling consisting of each intrinsic metabolic or transport process enables us to understand the disposition of drugs both at the organ level and at the level of the whole body by integrating a variety of experimental results into model parameters. This review focuses on the role of efflux transporters in the intestinal absorption and brain distribution of drugs, in addition to recent advances in predictive tools and methodologies.