Parvez Md Masud, Sadighi Armin, Ahn Yeseul, Keller Steve F, Enoru Julius O
Department of Quantitative, Translational & ADME Sciences (QTAS), AbbVie Biotherapeutics, San Francisco, CA 94080, USA.
Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S Coulter St., Amarillo, TX 79106, USA.
Pharmaceutics. 2023 Oct 16;15(10):2473. doi: 10.3390/pharmaceutics15102473.
Uptake drug transporters play a significant role in the pharmacokinetic of drugs within the brain, facilitating their entry into the central nervous system (CNS). Understanding brain drug disposition is always challenging, especially with respect to preclinical to clinical translation. These transporters are members of the solute carrier (SLC) superfamily, which includes organic anion transporter polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), and amino acid transporters. In this systematic review, we provide an overview of the current knowledge of uptake drug transporters in the brain and their contribution to drug disposition. Here, we also assemble currently available proteomics-based expression levels of uptake transporters in the human brain and their application in translational drug development. Proteomics data suggest that in association with efflux transporters, uptake drug transporters present at the BBB play a significant role in brain drug disposition. It is noteworthy that a significant level of species differences in uptake drug transporters activity exists, and this may contribute toward a disconnect in inter-species scaling. Taken together, uptake drug transporters at the BBB could play a significant role in pharmacokinetics (PK) and pharmacodynamics (PD). Continuous research is crucial for advancing our understanding of active uptake across the BBB.
摄取性药物转运体在药物在脑内的药代动力学中发挥着重要作用，促进药物进入中枢神经系统（CNS）。了解脑内药物处置一直具有挑战性，尤其是在从临床前到临床的转化方面。这些转运体是溶质载体（SLC）超家族的成员，其中包括有机阴离子转运多肽（OATP）、有机阴离子转运体（OAT）、有机阳离子转运体（OCT）和氨基酸转运体。在本系统评价中，我们概述了目前关于脑内摄取性药物转运体的知识及其对药物处置的贡献。在此，我们还汇总了目前基于蛋白质组学的人脑摄取转运体表达水平及其在转化药物开发中的应用。蛋白质组学数据表明，与外排转运体相关联，血脑屏障处存在的摄取性药物转运体在脑内药物处置中起重要作用。值得注意的是，摄取性药物转运体活性存在显著的种属差异，这可能导致种间比例换算出现脱节。综上所述，血脑屏障处的摄取性药物转运体可能在药代动力学（PK）和药效学（PD）中发挥重要作用。持续的研究对于推进我们对血脑屏障主动摄取的理解至关重要。
