Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: Comparison of unbound concentration ratios to in vivo P-glycoprotein efflux ratios
Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: Comparison of unbound concentration ratios to in vivo P-glycoprotein efflux ratios
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DOI：
10.1124/dmd.106.012294
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发表时间：
2007-04-01
影响因子：
3.9
通讯作者：
Pollack, Gary M.
中科院分区：
文献类型：
--
作者：
Kalvass, J. Cory;Maurer, Tristan S.;Pollack, Gary M.
P-糖蛋白（P-gp）缺陷小鼠模型用于评估P-gp介导的外排对药物中枢神经系统（CNS）分布的影响。稳态未结合血浆/未结合脑浓度比（[血浆]，（u）/[脑]，（u））是评估药物CNS分布的替代方法，与所涉及的机制无关。本研究的目的是比较根据体内P-gp外排率确定的CNS分布损害程度与根据[血浆]，（u）/[脑]，（u）比值确定的CNS分布损害程度。研究了34种药物的CNS分布，包括阿片类药物、曲坦类药物、蛋白酶抑制剂、抗组胺药和其他CNS分布或血脑屏障外排不良的临床相关药物。通过平衡透析测定血浆和脑未结合分数。K-p（脑）和P-gp外排率从文献中获得或通过实验测定。34种药物中有21种的P-gp外排率和[血浆]，（u）/[脑]，（u）比值一致（差异< 3倍）。然而，34种药物中有10种的[血浆]，（u）/[脑]，（u）比值显著超过P-gp外排率（> 4倍），表明其他非P-gp介导的机制可能限制这些药物的CNS分布。三种药物的P-gp外排率超过[血浆]，（u）/[脑]，（u）比3倍以上，表明存在主动摄取机制。这些观察结果表明，当P-gp以外的机制影响CNS分布时（非P-gp介导的外排、被动渗透性差、脑脊液整体流量、代谢或主动摄取），P-gp外排率可能低估或高估CNS分布损害。[血浆]，（u）/[脑]，（u）比值为评估药物的CNS分布提供了一种简单的机制独立的替代方法。
The P-glycoprotein (P-gp)-deficient mouse model is used to assess the influence of P-gp-mediated efflux on the central nervous system (CNS) distribution of drugs. The steady-state unbound plasma/unbound brain concentration ratio ([plasma],(u)/[brain],(u)) is an alternative method for assessing CNS distribution of drugs independent of the mechanism(s) involved. The objective of this study was to compare the degree of CNS distributional impairment determined from the in vivo P-gp efflux ratio with that determined from the [plasma],(u)/[brain],(u) ratio. CNS distribution of 34 drugs, including opioids, triptans, protease inhibitors, antihistamines, and other clinically relevant drugs with either poor CNS distribution or blood-brain barrier efflux, was studied. Plasma and brain unbound fractions were determined by equilibrium dialysis. K-p,(brain) and the P-gp efflux ratio were obtained from the literature or determined experimentally. The P-gp efflux ratio and the [plasma],(u)/[brain],(u) ratio were in concurrence (< 3-fold difference) for 21 of the 34 drugs. However, the [plasma],(u)/[brain],(u) ratio exceeded the P-gp efflux ratio substantially (> 4-fold) for 10 of the 34 drugs, suggesting that other, non-P-gp-mediated mechanism(s) may limit the CNS distribution of these drugs. The P-gp efflux ratio exceeded the [plasma],(u)/[brain],(u) ratio by more than 3-fold for three drugs, suggesting the presence of active uptake mechanism(s). These observations indicate that when mechanisms other than P-gp affect CNS distribution (non-P-gp-mediated efflux, poor passive permeability, cerebrospinal fluid bulk flow, metabolism, or active uptake), the P-gp efflux ratio may underestimate or overestimate CNS distributional impairment. The [plasma],(u)/[brain],(u) ratio provides a simple mechanism-independent alternative for assessing the CNS distribution of drugs.