期刊
PHARMACOLOGICAL REVIEWS
卷 75, 期 5, 页码 815-853出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/pharmrev.120.000025
关键词
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Drug efflux transporters at the blood-brain barrier limit drug delivery to the brain. Overcoming these transporters is a clinical challenge. Understanding the regulation mechanisms of these transporters is critical. This review summarizes the signaling pathways that regulate these transporters and discusses their clinical relevance.
drug efflux transporters ABCB1 and ABCG2 at the blood-brain barrier limit the delivery of drugs into the brain. Strategies to overcome ABCB1/ ABCG2 have been largely unsuccessful, which poses a tremendous clinical problem to successfully treat central nervous system (CNS) diseases. Understanding basic transporter biology, including intracellular regu-lation mechanisms that control these transporters, is critical to solving this clinical problem. In this comprehensive review, we summarize current knowledge on signaling pathways that regulate ABCB1/ABCG2 at the blood-brain barrier. In Section I, we give a historical overview on blood-brain barrier re-search and introduce the role that ABCB1 and ABCG2 play in this context. In Section II, we summarize the most important strategies that have been tested to overcome the ABCB1/ABCG2 efflux system at the blood -brain barrier. In Section III, the main component of this review, we provide detailed information on the signaling pathways that have been identified to control ABCB1/ABCG2 at the blood-brain barrier and their po-tential clinical relevance. This is followed by Section IV, where we explain the clinical implications of ABCB1/ABCG2 regulation in the context of CNS dis-ease. Lastly, in Section V, we conclude by highlighting examples of how transporter regulation could be tar-geted for therapeutic purposes in the clinic. Significance Statement--The ABCB1/ABCG2 drug efflux system at the blood-brain barrier poses a signifi-cant problem to successful drug delivery to the brain. The article reviews signaling pathways that regulate blood-brain barrier ABCB1/ABCG2 and could potentially be targeted for therapeutic purposes.
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