Structure-Brain Exposure Relationships in Rat and Human Using a Novel Data Set of Unbound Drug Concentrations in Brain Interstitial and Cerebrospinal Fluids
Structure-Brain Exposure Relationships in Rat and Human Using a Novel Data Set of Unbound Drug Concentrations in Brain Interstitial and Cerebrospinal Fluids
复制标题
DOI：
10.1021/jm901036q
复制
发表时间：
2009-10-22
影响因子：
7.3
通讯作者：
Antonsson, Madeleine
中科院分区：
文献类型：
--
作者：
Friden, Markus;Winiwarter, Susanne;Antonsson, Madeleine
应用新的实验方法测量了43种结构不同的药物在大鼠中的未结合脑-血浆浓度比（K-p、K-uu、K-brain）和未结合CSF-血浆浓度比（K-p、K-uu、K-CSF）。化学结构与K-p、K-uu、K-brain的关系以氢键为主。与基于总脑-血浆浓度比（logBB）的普遍理解相反，亲脂性不是未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、K-uu、K-brain的有用设计策略，但计算机预测模型的未来改进取决于主动药物转运的适应性。在大鼠中发现的结构-脑暴露关系也适用于人类，因为人类和大鼠K-p、K-uu、K-CSF的药物排序相似。对于39种药物中的33种，K-p、K-uu、K-CSF在大鼠中的K-p、K-uu、K-brain的3倍范围内，这一跨种属比较得到了支持。然而，还观察到K-p、K-uu、K-CSF过度预测了高度外排药物的K-p、K-uu、K-brain，表明与血脑屏障相比，血-脑脊液屏障的外排能力较低。
New experimental methodologies were applied to measure the unbound brain-to-plasma concentration ratio (K-p,K-uu,K-brain) and the unbound CSF-to-plasma concentration ratio (K-p,K-uu,K-CSF) in rats for 43 structurally diverse drugs. The relationship between chemical structure and K-p,K-uu,K-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,K-uu,K-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,K-uu,K-CSF. This cross-species comparison was supported by K-p,K-uu,K-CSF being within 3-fold of K-p,K-uu,K-brain in the rat for 33 of 39 drugs. It was, however, also observed that K-p,K-uu,K-CSF overpredicts K-p,K-uu,K-brain for highly effluxed drugs, indicating lower efflux capacity of the blood-cerebrospinal fluid barrier compared to the blood-brain barrier.