P-糖蛋白
血脑屏障
药物发现
运输机
流出
药理学
药品
生物
中枢神经系统
ATP结合盒运输机
药代动力学
医学
神经科学
生物信息学
抗药性
生物化学
基因
多重耐药
遗传学
作者
Benoit Cox,Johan Nicolaï,Beth Williamson
摘要
The blood-brain barrier (BBB) expresses a high abundance of transporters, particularly P-glycoprotein (P-gp), that regulate endogenous and exogenous molecule uptake and removal of waste. This review discusses key drug metabolism and pharmacokinetic considerations for the efflux transporter P-gp at the BBB in drug discovery and development. We highlight the differences in P-gp expression and protein levels across species but the limited observations of species-specific substrates. Given the impact of age and disease on BBB biology, we summarise the modulation of P-gp for several neurological disorders and ageing and exemplify several disease-specific hurdles or opportunities for drug exposure in the brain. Furthermore, the review includes observations of CNS-related drug-drug interactions due to the inhibition or induction of P-gp at the BBB in animal studies and humans and the need for continued evaluation especially for compounds with a narrow therapeutic window. This review focusses primarily on small molecules but also considers the impact of new chemical entities, particularly beyond Ro5 molecules and their potential to be recognised as P-gp substrates as well as advanced drug delivery systems which offer an alternative approach to achieve and sustain central nervous system exposure.
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