Platform Technology and Science, GlaxoSmithKline R&D Center, Shanghai, China.
Platform Technology and Science, GlaxoSmithKline R&D Center, Shanghai, China.
Drug Discov Today. 2018 Jul;23(7):1357-1372. doi: 10.1016/j.drudis.2018.03.002. Epub 2018 Mar 13.
Recent years have seen a paradigm shift away from optimizing the brain:blood concentration ratio toward the more relevant brain:blood unbound concentration ratio (K) in CNS drug discovery. Here, we review the recent developments in the in silico and in vitro model systems to predict the K of discovery compounds with special emphasis on the in-vitro-in-vivo correlation. We also discuss clinical 'translation' of rodent K and highlight the future directions for improvement in brain penetration prediction. Important in this regard are in silico K models built on larger datasets of high quality, calibration and deeper understanding of experimental in vitro transporter systems, and better understanding of blood-brain barrier transporters and their in vivo relevance aside from P-gp and BCRP.
近年来，人们的观念从优化脑：血浓度比值逐渐转变为更相关的脑：血未结合浓度比值（K），这在中枢神经系统药物发现中尤为明显。本文综述了预测发现化合物 K 的计算和体外模型系统的最新进展，特别强调了体外-体内相关性。我们还讨论了啮齿动物 K 的临床“转化”，并强调了提高脑渗透预测的未来方向。在这方面，重要的是建立在高质量、校准和对实验性体外转运体系统更深入理解的大型数据集上的计算 K 模型，以及除了 P-糖蛋白和 BCRP 之外，对血脑屏障转运体及其体内相关性的更好理解。
