Predictive Pharmacology Group, Systems Pharmacology and Pharmacy, LACDR, Leiden University, Leiden, The Netherlands.
Translational PKPD Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Clin Pharmacol Ther. 2022 Apr;111(4):758-773. doi: 10.1002/cpt.2545. Epub 2022 Feb 27.
This review addresses questions on how to accomplish successful central nervous system (CNS) drug delivery (i.e., having the right concentration at the right CNS site, at the right time), by understanding the rate and extent of blood-brain barrier (BBB) transport and intra-CNS distribution in relation to CNS target site(s) exposure. To this end, we need to obtain and integrate quantitative and connected data on BBB using the Combinatory Mapping Approach that includes in vivo and ex vivo animal measurements, and the physiologically based comprehensive LEICNSPK3.0 mathematical model that can translate from animals to humans. For small molecules, slow diffusional BBB transport and active influx and efflux BBB transport determine the differences between plasma and CNS pharmacokinetics. Obviously, active efflux is important for limiting CNS drug delivery. Furthermore, liposomal formulations of small molecules may to a certain extent circumvent active influx and efflux at the BBB. Interestingly, for CNS pathologies, despite all reported disease associated BBB and CNS functional changes in animals and humans, integrative studies typically show a lack of changes on CNS drug delivery for the small molecules. In contrast, the understanding of the complex vesicle-based BBB transport modes that are important for CNS delivery of large molecules is in progress, and their BBB transport seems to be significantly affected by CNS diseases. In conclusion, today, CNS drug delivery of small drugs can be well assessed and understood by integrative approaches, although there is still quite a long way to go to understand CNS drug delivery of large molecules.
本综述探讨了如何通过了解血脑屏障 (BBB) 转运和脑内分布与中枢神经系统 (CNS) 靶部位暴露的关系，实现成功的中枢神经系统 (CNS) 药物递送（即，在正确的 CNS 部位、在正确的时间具有正确的浓度）的问题。为此，我们需要使用组合映射方法获得和整合有关 BBB 的定量和相关数据，该方法包括体内和体外动物测量以及基于生理学的综合 LEICNSPK3.0 数学模型，该模型可以从动物转化为人类。对于小分子，BBB 转运的缓慢扩散性和主动内流和外排 BBB 转运决定了血浆和中枢神经系统药代动力学之间的差异。显然，主动外排对于限制中枢神经系统药物递送很重要。此外，小分子的脂质体制剂在一定程度上可以规避 BBB 处的主动内流和外排。有趣的是，对于中枢神经系统疾病，尽管在动物和人类中都报道了与疾病相关的 BBB 和中枢神经系统功能变化，但综合研究通常表明小分子的中枢神经系统药物递送没有变化。相比之下，对于大分子的中枢神经系统递送，重要的基于囊泡的 BBB 转运模式的复杂理解正在进行中，并且它们的 BBB 转运似乎受到中枢神经系统疾病的显著影响。总之，尽管仍有很长的路要走才能理解大分子的中枢神经系统药物递送，但今天可以通过综合方法很好地评估和理解小分子的中枢神经系统药物递送。
