Development of a physiologically based pharmacokinetic model for the rat central nervous system and determination of an in vitro-in vivo scaling methodology for the blood-brain barrier permeability of two transporter substrates, morphine and oxycodone
Development of a physiologically based pharmacokinetic model for the rat central nervous system and determination of an in vitro-in vivo scaling methodology for the blood-brain barrier permeability of two transporter substrates, morphine and oxycodone
复制标题
DOI：
10.1002/jps.23266
复制
发表时间：
2012-11-01
影响因子：
3.8
通讯作者：
Decleves, Xavier
中科院分区：
文献类型：
--
作者：
Ball, Kathryn;Bouzom, Francois;Decleves, Xavier
建立了一个基于生理学的全身药代动力学（PBPK）模型，用于预测大鼠脑中未结合药物的浓度-时间曲线，其中通过将控制血脑屏障（BBB）转移速率（渗透性）的参数与脑结合分离来机械地处理药物穿过BBB的转移。提出了一种基于Caco-2细胞渗透性的体外体内缩放策略来外推该渗透性的活性转运蛋白驱动的组分，其中通过将模型拟合到大鼠体内曲线来估计相对活性因子RAF。该比例因子可以解释为对于给定的体外系统中的给定药物，体外系统和体内BBB之间的转运蛋白活性的比率。选择吗啡和羟考酮分别作为BBB定位的流出和流入转运蛋白的底物来评价该策略。在使用大鼠模型估计其各自的RAF后，使用PBPK模型来模拟假设相同RAF的人脑浓度分布，并讨论了其含义。(C)2012 Wiley Periodicals，Inc.和American Pharmacologist Association J Pharm Sci 101：42774292，2012
A whole-body physiologically based pharmacokinetic (PBPK) model was developed for the prediction of unbound drug concentration-time profiles in the rat brain, in which drug transfer across the bloodbrain barrier (BBB) was treated mechanistically by separating the parameters governing the rate (permeability) of BBB transfer from brain binding. An in vitroin vivo scaling strategy based on Caco-2 cell permeability was proposed to extrapolate the active transporter-driven component of this permeability, in which a relative activity factor, RAF, was estimated by fitting the model to rat in vivo profiles. This scaling factor could be interpreted as the ratio of transporter activity between the in vitro system and the in vivo BBB, for a given drug in a given in vitro system. Morphine and oxycodone were selected to evaluate this strategy, as substrates of BBB-located efflux and influx transporters, respectively. After estimation of their respective RAFs using the rat model, the PBPK model was used to simulate human brain concentration profiles assuming the same RAF, and the implications of this were discussed. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:42774292, 2012