Blood-brain barrier P450 enzymes and multidrug transporters in drug resistance: a synergistic role in neurological diseases.
Blood-brain barrier P450 enzymes and multidrug transporters in drug resistance: a synergistic role in neurological diseases.
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DOI：
10.2174/138920011798357051
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发表时间：
2011-10
影响因子：
2.3
通讯作者：
Marchi N
中科院分区：
文献类型：
--
作者：
Ghosh C;Puvenna V;Gonzalez-Martinez J;Janigro D;Marchi N
药物渗透到中枢神经系统（CNS）是由血脑屏障（BBB）控制的。尽管已经制定了许多规避 BBB 和改善药物获取的策略，但中枢神经系统疾病的耐药性仍然是一个未解决的临床问题。我们在此回顾健康或病理性 BBB 影响大脑中药物分布的机制，重点关注 P450 代谢酶和多药物转运蛋白 (MDT) 的作用。除了经典的肝脏和肠道生物转化途径外，P450酶的中枢神经系统表达可能具有药代动力学和药效学意义，发挥代谢活性并将母体药物转化为特定产物。我们提出这些机制在中枢神经系统耐药病理学（包括难治性癫痫）中发挥重要作用。脑血管血流动力学条件的变化可影响P450酶和MDT蛋白的表达。在开发体外实验方法来重现 BBB 的生理或病理特性时，应考虑到这一点。最后，讨论了患病大脑中 P450 和 MDT 表达与细胞存活之间的联系。
Drug penetration into the central nervous system (CNS) is controlled by the blood-brain barrier (BBB). Even though a number of strategies to circumvent the BBB and to improve drug access have been developed, drug resistance in CNS diseases remains an unmet clinical problem. We here review the mechanisms by which a healthy or pathological BBB influences drug distribution in the brain, with emphasis on the role of P450 metabolic enzymes and multi-drug transporter (MDT) proteins. In addition to the classic hepatic and gut biotransformation pathways, CNS expression of P450 enzymes may bear pharmacokinetic and pharmacodynamic significance exerting a metabolic activity and transforming parent drugs into specific products. We propose these mechanisms to play a major role in CNS drug resistant pathologies including refractory forms of epilepsy. Changes in the cerebrovascular hemodynamic conditions can affect expression of P450 enzymes and MDT proteins. This should be taken into account when developing in vitro experimental approaches to reproduce the physiological or pathological properties of the BBB. Finally, a link between P450 and MDT expression in the diseased brain and cell survival is discussed.