Rational Use of Plasma Protein and Tissue Binding Data in Drug Design
Rational Use of Plasma Protein and Tissue Binding Data in Drug Design
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DOI：
10.1021/jm5007935
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发表时间：
2014-10-23
影响因子：
7.3
通讯作者：
Hop, Cornelis E. C. A.
中科院分区：
文献类型：
--
作者：
Liu, Xingrong;Wright, Matthew;Hop, Cornelis E. C. A.
这是一个普遍接受的假设，即只有未结合的药物分子才能与其靶标相互作用。因此，优化化合物结构以提高体内游离药物浓度是药物设计的目标之一。本文从理论分析和实验观察两个方面阐述了血浆蛋白结合量低并不一定会导致体内游离血浆浓度较高。同样，低结合的脑组织并不会导致体内高的非结合脑组织浓度。相反，低内源性清除量会导致体内游离血浆浓度升高，而血脑屏障外流转运活性低则会导致脑内游离浓度升高。血浆蛋白和脑组织结合是了解药物的药代动力学、药效学和毒性的重要参数，但在药物设计中这些参数不应作为优化的目标。
It is a commonly accepted assumption that only unbound drug molecules are available to interact with their targets. Therefore, one of the objectives in drug design is to optimize the compound structure to increase in vivo unbound drug concentration. In this review, theoretical analyses and experimental observations are presented to illustrate that low plasma protein binding does not necessarily lead to high in vivo unbound plasma concentration. Similarly, low brain tissue binding does not lead to high in vivo unbound brain tissue concentration. Instead, low intrinsic clearance leads to high in vivo unbound plasma concentration, and low efflux transport activity at the bloodbrain barrier leads to high unbound brain concentration. Plasma protein and brain tissue binding are very important parameters in understanding pharmacokinetics, pharmacodynamics, and toxicities of drugs, but these parameters should not be targeted for optimization in drug design