Mimicking brain tissue binding in an in vitro model of the blood-brain barrier illustrates differences between in vitro and in vivo methods for assessing the rate of brain penetration
Mimicking brain tissue binding in an in vitro model of the blood-brain barrier illustrates differences between in vitro and in vivo methods for assessing the rate of brain penetration
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DOI：
10.1016/j.ejpb.2018.03.007
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发表时间：
2018-06-01
影响因子：
4.9
通讯作者：
Culot, Maxime
中科院分区：
文献类型：
--
作者：
Heymans, Marjolein;Sevin, Emmanuel;Culot, Maxime
几十年来，体外评估药物递送至中枢神经系统（CNS）的速率已被用于预测CNS候选药物是否可能以有效剂量达到其位于脑实质内的药理学靶点。因此，体外血脑屏障（BBB）模型的预测价值通常通过比较体外BBB渗透性（通常引用为内皮渗透系数（P-e）或表观渗透性（P-app））与体内测量的BBB渗透速率来评估，后者通常在啮齿动物中评估。（DMPK部门，Sodertalje，Sweden），使用牛体外BBB模型测定了27种市售CNS药物的体外BBB渗透性（P（app）和P-e），并与通过大鼠原位脑灌注获得的它们的体内渗透性（P-vivo）进行比较。后者来自萨默菲尔德等人（2007）的已发表数据。该比较证实了先前的报告，显示亲水性化合物的体外/体内相关性较强，其特征在于脑组织结合较低，亲脂性化合物的相关性较弱，其特征在于脑组织结合较高。这一观察结果可以解释为脑组织结合对药物进入CNS的体内吸收的影响以及体外没有可能的脑组织结合。在体外BBB模型中使用胶质细胞（GC）来模拟脑组织结合并引入体外BBB渗透性（P-vitro）的新计算方法。导致对于整套化合物，体外和体内BBB渗透速率之间的强相关性。这些发现可能有助于进一步从体外到体内外推CNS候选药物。
Assessing the rate of drug delivery to the central nervous system (CNS) in vitro has been used for decades to predict whether CNS drug candidates are likely to attain their pharmacological targets, located within the brain parenchyma, at an effective dose. The predictive value of in vitro blood-brain barrier (BBB) models is therefore frequently assessed by comparing in vitro BBB permeability, usually quoted as the endothelial permeability coefficient (P-e) or apparent permeability (P-app), to their rate of BBB permeation measured in vivo, the latter being commonly assessed in rodents.In collaboration with AstraZeneca (DMPK department, Sodertalje, Sweden), the in vitro BBB permeability (P(app )and P-e) of 27 marketed CNS drugs has been determined using a bovine in vitro BBB model and compared to their in vivo permeability (P-vivo), obtained by rat in-situ brain perfusion. The latter was taken from published data from Summerfield et al. (2007).This comparison confirmed previous reports, showing a strong in vitro/in vivo correlation for hydrophilic compounds, characterized by low brain tissue binding and a weak correlation for lipophilic compounds, characterized by high brain tissue binding. This observation can be explained by the influence of brain tissue binding on the uptake of drugs into the CNS in vivo and the absence of possible brain tissue binding in vitro.The use of glial cells (GC) in the in vitro BBB model to mimic brain tissue binding and the introduction of a new calculation method for in vitro BBB permeability (P-vitro) resulted in a strong correlation between the in vitro and in vivo rate of BBB permeation for the whole set of compounds. These findings might facilitate further in vitro to in vivo extrapolation for CNS drug candidates.