Fridén Markus, Winiwarter Susanne, Jerndal Gunilla, Bengtsson Ola, Wan Hong, Bredberg Ulf, Hammarlund-Udenaes Margareta, Antonsson Madeleine
Discovery DMPK, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden.
J Med Chem. 2009 Oct 22;52(20):6233-43. doi: 10.1021/jm901036q.
New experimental methodologies were applied to measure the unbound brain-to-plasma concentration ratio (K(p,uu,brain)) and the unbound CSF-to-plasma concentration ratio (K(p,uu,CSF)) in rats for 43 structurally diverse drugs. The relationship between chemical structure and K(p,uu,brain) was dominated by hydrogen bonding. Contrary to popular understanding based on the total brain-to-plasma concentration ratio (logBB), lipophilicity was not a determinant of unbound brain exposure. Although changing the number of hydrogen bond acceptors is a useful design strategy for optimizing K(p,uu,brain), future improvement of in silico prediction models is dependent on the accommodation of active drug transport. The structure-brain exposure relationships found in the rat also hold for humans, since the rank order of the drugs was similar for human and rat K(p,uu,CSF). This cross-species comparison was supported by K(p,uu,CSF) being within 3-fold of K(p,uu,brain) in the rat for 33 of 39 drugs. It was, however, also observed that K(p,uu,CSF) overpredicts K(p,uu,brain) for highly effluxed drugs, indicating lower efflux capacity of the blood-cerebrospinal fluid barrier compared to the blood-brain barrier.
采用新的实验方法测定了43种结构各异的药物在大鼠体内的非结合脑血浓度比（K(p,uu,brain)）和非结合脑脊液血浓度比（K(p,uu,CSF)）。化学结构与K(p,uu,brain)之间的关系主要由氢键主导。与基于总脑血浓度比（logBB）的普遍认识相反，亲脂性并非非结合脑暴露的决定因素。虽然改变氢键受体的数量是优化K(p,uu,brain)的一种有用设计策略，但计算机预测模型的未来改进取决于对活性药物转运的考量。在大鼠中发现的结构脑暴露关系在人类中也成立，因为人类和大鼠的K(p,uu,CSF)药物排名顺序相似。这种跨物种比较得到了支持，在大鼠中，39种药物中有33种的K(p,uu,CSF)在K(p,uu,brain)的3倍以内。然而，还观察到，对于高外排药物，K(p,uu,CSF)高估了K(p,uu,brain)，这表明血脑脊液屏障的外排能力低于血脑屏障。
