Kalvass J Cory, Maurer Tristan S, Pollack Gary M
C.B. 7360, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
Drug Metab Dispos. 2007 Apr;35(4):660-6. doi: 10.1124/dmd.106.012294. Epub 2007 Jan 19.
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.
P-糖蛋白（P-gp）缺陷小鼠模型用于评估P-gp介导的外排在药物中枢神经系统（CNS）分布中的影响。稳态未结合血浆/未结合脑浓度比（[血浆]u/[脑]u）是一种独立于所涉及机制来评估药物CNS分布的替代方法。本研究的目的是比较通过体内P-gp外排率确定的CNS分布损害程度与通过[血浆]u/[脑]u比值确定的程度。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、抗组胺药以及其他CNS分布较差或存在血脑屏障外排的临床相关药物。通过平衡透析测定血浆和脑的未结合分数。K（p，脑）和P-gp外排率从文献中获取或通过实验确定。34种药物中的21种，P-gp外排率与[血浆]u/[脑]u比值一致（差异<3倍）。然而，34种药物中的10种，[血浆]u/[脑]u比值显著超过P-gp外排率（>4倍），这表明其他非P-gp介导的机制可能限制了这些药物的CNS分布。三种药物的P-gp外排率超过[血浆]u/[脑]u比值3倍以上，表明存在主动摄取机制。这些观察结果表明，当除P-gp之外的机制影响CNS分布（非P-gp介导的外排、被动通透性差、脑脊液大量流动、代谢或主动摄取）时，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、独立于机制的替代方法。
