Influence of nonspecific brain and plasma binding on CNS exposure: Implications for rational drug discovery
Influence of nonspecific brain and plasma binding on CNS exposure: Implications for rational drug discovery
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DOI：
10.1002/bdd.325
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发表时间：
2002-11-01
影响因子：
2.1
通讯作者：
Maurer, TS
中科院分区：
文献类型：
--
作者：
Kalvass, JC;Maurer, TS
在大鼠中检查了18种专利化合物的相对血浆、脑和脑脊液（CSF）暴露量以及血浆和脑中的未结合分数。研究了体内脑-血浆比和体外血浆-脑未结合分数（fu）之间的关系。此外，血浆fu和脑fu分别检查其与体内CSF-血浆和CSF-脑比率的关系。根据是否存在主动外排描述结果。最后，在FVB与MDR 1a/1b基因敲除小鼠中对选定的P-糖蛋白（Pgp）底物进行了相同的比较。对于没有主动外排迹象的9种化合物，在脑-血浆暴露量与血浆-脑fu比值（r（2）= 0.98）、CSF-脑暴露量与脑fu比值（r（2）= 0.72）和CSF-血浆暴露量与血浆fu比值（r（2）= 0.82）之间观察到预测相关性。对于具有主动外排适应症的9种化合物，非特异性结合数据倾向于过度预测脑-血浆和CSF-血浆暴露比。有趣的是，CSF-脑暴露比始终低于脑fu对该组的预测。使用选择的Pgp底物，证明脑-血浆暴露比与MDR 1a/1b敲除小鼠中血浆-脑FU比预测的相同。在FVB小鼠中，血浆-脑fu超过预测的脑-血浆暴露比，其程度与MDR 1a/1b和FVB小鼠之间脑-血浆暴露比的差异相同。在大鼠中获得了一致的结果，表明种属之间具有相似的动力学行为。这些数据说明了对相对组织结合（血浆、脑）的理解如何能够允许对确定CNS暴露的活性过程进行定量检查。这种方法的普遍适用性提供了优于物种和机制的具体方法。版权所有（C）2002约翰威利父子有限公司
Relative plasma, brain and cerebrospinal fluid (CSF) exposures and unbound fractions in plasma and brain were examined for 18 proprietary compounds in rats. The relationship between in vivo brain-to-plasma ratio and in vitro plasma-to-brain unbound fraction (fu) was examined. In addition, plasma fu and brain fu were examined for their relationship to in vivo CSF-to-plasma and CSF-to-brain ratios, respectively. Findings were delineated based on the presence or absence of active efflux. Finally, the same comparisons were examined in FVB vs. MDR 1a/1b knockout mice for a selected P-glycoprotein (Pgp) substrate. For the nine compounds without indications of active efflux, predictive correlations were observed between ratios of brain-to-plasma exposure and plasma-to-brain fu (r(2) = 0.98), CSF-to-brain exposure vs. brain fu (r(2) = 0.72), and CSF-to-plasma exposure vs. plasma fu (r(2) = 0.82). For the nine compounds with indications of active efflux, nonspecific binding data tended to over predict the brain-to-plasma and CSF-to-plasma exposure ratios. Interestingly, CSF-to-brain exposure ratio was consistently under predicted by brain fu for this set. Using a select Pgp substrate, it was demonstrated that the brain-to-plasma exposure ratio was identical to that predicted by plasma-to-brain fu ratio in MDR 1a/1b knockout mice. In FVB mice, plasma-to-brain fu over predicted brain-to-plasma exposure ratio to the same degree as the difference in brain-to-plasma exposure ratio between MDR 1a/1b and FVB mice. Consistent results were obtained in rats, suggesting a similar kinetic behavior between species. These data illustrate how an understanding of relative tissue binding (plasma, brain) can allow for a quantitative examination of active processes that determine CNS exposure. The general applicability of this approach offers advantages over species- and mechanism-specific approaches. Copyright (C) 2002 John Wiley Sons, Ltd.