Summerfield S G, Lucas A J, Porter R A, Jeffrey P, Gunn R N, Read K R, Stevens A J, Metcalf A C, Osuna M C, Kilford P J, Passchier J, Ruffo A D
Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Harlow, UK.
Xenobiotica. 2008 Dec;38(12):1518-35. doi: 10.1080/00498250802499459.
The penetration of drugs into the central nervous system is a composite of both the rate of drug uptake across the blood-brain barrier and the extent of distribution into brain tissue compartments. Clinically, positron emission tomography (PET) is the primary technique for deriving information on drug biodistribution as well as target receptor occupancy. In contrast, rodent models have formed the basis for much of the current understanding of brain penetration within pharmaceutical Drug Discovery. Linking these two areas more effectively would greatly improve the translation of candidate compounds into therapeutic agents. This paper examines two of the major influences on the extent of brain penetration across species, namely plasma protein binding and brain tissue binding. An excellent correlation was noted between unbound brain fractions across species (R(2) > 0.9 rat, pig, and human, n = 21), which is indicative of the high degree of conservation of the central nervous system environment. In vitro estimates of human brain-blood or brain-plasma ratios of marketed central nervous system drugs and PET tracers agree well with in vivo values derived from clinical PET and post-mortem studies. These results suggest that passive diffusion across the blood-brain barrier is an important process for many drugs in humans and highlights the possibility for improved prediction of brain penetration across species.
药物进入中枢神经系统的过程是药物通过血脑屏障摄取速率和在脑组织各部分分布程度的综合体现。临床上，正电子发射断层扫描（PET）是获取药物生物分布以及靶点受体占有率信息的主要技术。相比之下，啮齿动物模型构成了目前药物研发领域对脑内渗透理解的大部分基础。更有效地将这两个领域联系起来将极大地促进候选化合物向治疗药物的转化。本文研究了跨物种脑内渗透程度的两个主要影响因素，即血浆蛋白结合和脑组织结合。研究发现跨物种的游离脑部分之间存在极好的相关性（大鼠、猪和人类的R²>0.9，n = 21），这表明中枢神经系统环境具有高度的保守性。市售中枢神经系统药物和PET示踪剂的人脑-血或脑-血浆比率的体外估计值与临床PET和尸检研究得出的体内值非常吻合。这些结果表明，对于许多人类药物来说，通过血脑屏障的被动扩散是一个重要过程，并突出了改进跨物种脑内渗透预测的可能性。
