Inserm, U842, faculté de médecine Laennec, université de Lyon, université Lyon-1, UMR-S842, 69008 Lyon, France.
Rev Neurol (Paris). 2009 Dec;165(12):1029-38. doi: 10.1016/j.neurol.2009.09.011.
The low cerebral bioavailability of various drugs is a limiting factor in the treatment of neurological diseases. The restricted penetration of active compounds into the brain is the result of the same mechanisms that are central to the maintenance of brain extracellular fluid homeostasis, in particular from the strict control imposed on exchanges across the blood-brain interfaces. Direct drug entry into the brain parenchyma occurs across the cerebral microvessel endothelium that forms the blood-brain barrier. In addition, local drug concentration measurements and cerebral imaging have clearly shown that the choroid plexuses - the main site of the blood-cerebrospinal fluid (CSF) barrier - together with the CSF circulatory system also play a significant role in setting the cerebral bioavailability of drugs and contrast agents. The entry of water-soluble therapeutic compounds into the brain is impeded by the presence of tight junctions that seal the cerebral endothelium and the choroidal epithelium. The cerebral penetration of many of the more lipid-soluble molecules is also restricted by various classes of efflux transporters that are differently distributed among both blood-brain interfaces, and comprise either multidrug resistance proteins of the ATP-binding cassette superfamily or transporters belonging to several solute carrier families. Expression of these transporters is regulated in various pathophysiological situations, such as epilepsy and inflammation, with pharmacological consequences that have yet to be clearly elucidated. As for brain tumour treatments, their efficacy may be affected not only by the intrinsic resistance of tumour cells, but also by endothelial efflux transporters which exert an even greater impact than the integrity of the endothelial tight junctions. Relevant to paediatric neurological treatments, both blood-brain interfaces are known to develop a tight phenotype very early on in postnatal development, but the developmental profile of efflux transporters still needs to be assessed in greater detail. Finally, the exact role of the ependyma and pia-glia limitans in controlling drug exchanges between brain parenchyma and CSF deserves further attention to allow more precise predictions of cerebral drug disposition and therapeutic efficacy.
各种药物的脑内生物利用度低是治疗神经系统疾病的一个限制因素。活性化合物进入大脑的受限渗透是维持脑细胞外液平衡的相同机制的结果，特别是对跨越血脑界面的交换严格控制的结果。药物直接进入脑实质是通过形成血脑屏障的脑微血管内皮细胞进行的。此外，局部药物浓度测量和脑成像清楚地表明，脉络丛 - 血脑脊液（CSF）屏障的主要部位 - 以及 CSF 循环系统，也在确定药物和对比剂的脑生物利用度方面发挥着重要作用。亲水性治疗化合物进入大脑的通道受到紧密连接的阻碍，这些连接封闭了脑内皮细胞和脉络丛上皮细胞。许多更具脂溶性的分子进入大脑的渗透也受到各种类型的外排转运体的限制，这些转运体在两个血脑界面之间分布不同，包括 ABC 超家族的多药耐药蛋白或属于几个溶质载体家族的转运体。这些转运体的表达在各种病理生理情况下受到调节，如癫痫和炎症，其药理后果尚未得到明确阐明。至于脑肿瘤治疗，其疗效不仅受肿瘤细胞固有耐药性的影响，还受内皮外排转运体的影响，内皮外排转运体的影响甚至大于内皮紧密连接的完整性。与儿科神经治疗相关的是，已知两个血脑界面在出生后发育的早期就会发展出紧密表型，但外排转运体的发育情况仍需要更详细地评估。最后，内皮层和软脑膜-软脊膜界限在控制脑实质和 CSF 之间药物交换的确切作用值得进一步关注，以允许更精确地预测脑药物处置和治疗效果。
