The blood–brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex regulation of Pgp expression and functional activity at the BBB with an emphasis on recent studies from our laboratory. In addition to traditional processes such as transcriptional regulation and posttranscriptional or posttranslational modification of Pgp expression and functionality, novel mechanisms such as intra- and intercellular Pgp trafficking and intracellular Pgp-mediated lysosomal sequestration in BBB endothelial cells with subsequent disposal by blood neutrophils are discussed. These intrinsic mechanisms of active drug extrusion at the BBB are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the treatment of brain diseases and enhance drug delivery to the brain.

中文翻译：

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活性药物在血脑屏障中的新的内在机制：增强药物向大脑的传递的潜在目标？

血脑屏障（BBB）限制了几种脑部疾病的药物治疗。除了血脑屏障的结构和代谢特性外，ATP驱动的药物外排转运蛋白P-糖蛋白（Pgp）是血脑屏障的选择性守门人。因此，这是药物进入大脑的主要障碍。在这里，我们回顾了BBB对Pgp表达和功能活性的复杂调控，重点是我们实验室的最新研究。除了传统的过程（例如转录调控以及Pgp表达和功能的转录后或翻译后修饰）之外，还讨论了新颖的机制，例如BBB内皮细胞中细胞内和细胞间Pgp转运以及细胞内Pgp介导的溶酶体隔离以及随后被血液中性粒细胞处理的问题。