Department of Medical Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ 85724-5050, USA.
Pharmacol Rev. 2013 Jan 23;65(1):291-314. doi: 10.1124/pr.112.005991. Print 2013 Jan.
Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion-transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia.
药物渗透有限是治疗中枢神经系统（CNS）疾病（包括疼痛和脑缺氧）时经常遇到的障碍。在过去的几年中，脑的生化特性（即脑屏障部位的紧密连接蛋白复合物、流入和流出转运体的表达）已被证明直接参与决定治疗剂向中枢神经系统的渗透；然而，绝大多数这些研究都集中在理解那些阻止药物进入中枢神经系统的机制上。最近，这种模式已经转向确定和描述促进中枢神经系统药物输送的脑靶标。这些靶标包括有机阴离子转运多肽（人 OATPs；啮齿动物 Oatps），这是一组在脑中内源性表达的、与药物摄取有关的非钠依赖性转运体。OATP/Oatp 的底物包括在治疗疼痛和/或脑缺氧方面有效的药物（即阿片样肽、3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂）。这清楚地表明，OATP/Oatp 同工型是可行的转运体靶标，可以用于优化药物向大脑的输送，从而改善中枢神经系统疾病的治疗。这篇综述总结了这一领域的最新知识，并强调了治疗靶向 OATP/Oatp 同工型在促进中枢神经系统药物输送和分布方面的潜力。此外，本综述中提供的信息将指出可用于治疗疼痛和脑缺氧的新策略。
