Examining the Uptake of Central Nervous System Drugs and Candidates across the Blood-Brain Barrier
Examining the Uptake of Central Nervous System Drugs and Candidates across the Blood-Brain Barrier
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DOI：
10.1124/jpet.116.232447
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发表时间：
2016-08-01
影响因子：
3.5
通讯作者：
Liu, Houfu
中科院分区：
文献类型：
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作者：
Summerfield, Scott G.;Zhang, Yanyan;Liu, Houfu
通过血脑屏障(K-p，K-Uu)评估游离药物浓度的平衡性已逐渐取代了基于脑组织中总浓度与血液的比率(K-p)的分配系数。在这里，对一组中枢神经系统(CNS)靶向化合物在大鼠和P-糖蛋白(P-gp)基因敲除小鼠中的体内脑分布进行了研究。几种中枢神经系统药物的特征是K-p，K-Uu值大于1，推测促进了对啮齿动物血脑屏障(BBB)的摄取。其中K-p，K-Uu在P-gp基因敲除时也增加到1以上的例子，突出了该参数在促进血脑屏障摄取、外排和被动扩散方面的综合性质。几个具有高K(p，Uu)值的分子共享共同的结构元素，而跨BBB的摄取似乎在CNS靶向药物集中比在当前的铅优化范例中产生的化学模板更普遍。在急性与稳态数据和跨物种差异的背景下，讨论了识别高K(p，Uu)化合物的挑战。显然，需要对人脑K-P、K-UU建立更好的预测模型。
Assessing the equilibration of the unbound drug concentrations across the blood-brain barrier (K-p,K-uu) has progressively replaced the partition coefficient based on the ratio of the total concentration in brain tissue to blood (K-p). Here, in vivo brain distribution studies were performed on a set of central nervous system (CNS)-targeted compounds in both rats and P-glycoprotein (P-gp) genetic knockout mice. Several CNS drugs are characterized by K-p,K-uu values greater than unity, inferring facilitated uptake across the rodent blood-brain barrier (BBB). Examples are shown in which K-p,K-uu also increases above unity on knockout of P-gp, highlighting the composite nature of this parameter with respect to facilitated BBB uptake, efflux, and passive diffusion. Several molecules with high K(p,uu )values share common structural elements, whereas uptake across the BBB appears more prevalent in the CNS-targeted drug set than the chemical templates being generated within the current lead optimization paradigm. Challenges for identifying high K(p,uu )compounds are discussed in the context of acute versus steady-state data and cross-species differences. Evidently, there is a need for better predictive models of human brain K-p,K-uu.