Riley R J, Foley S A, Barton P, Soars M G, Williamson B
a Evotec , Abingdon , UK.
b School of Life Sciences , University of Nottingham , Nottingham , UK.
Expert Opin Drug Metab Toxicol. 2016;12(2):201-16. doi: 10.1517/17425255.2016.1132308. Epub 2016 Jan 8.
The key role of transporter biology in both the manifestation and treatment of disease is now firmly established. Experiences of sub-optimal drug exposure due to drug-transporter interplay have supported incorporation of studies aimed at understanding the interactions between compounds and drug transporters much earlier in drug discovery. While drug transporters can impact the most pivotal pharmacokinetic parameter with respect to human dose and exposure projections, clearance, at a renal or hepatobiliary level, the latter will form the focus of this perspective.
A synopsis of guidelines on which transporters to study together with an overview of the currently available toolkit is presented. A perspective on when to conduct studies with various hepatic transporters is also provided together with structural "alerts" which should prompt early investigation.
Great progress has been made in individual laboratories and via consortia to understand the role of drug transporters in disease, drug disposition, drug-drug interactions and toxicity. A systematic analysis of the value posed by the available approaches and an inter-lab comparison now seems warranted. The emerging ability to use physico-chemical properties to guide future screening cascades promises to revolutionise the efficiency of early drug discovery.
转运体生物学在疾病的表现和治疗中所起的关键作用现已得到明确确立。由于药物与转运体相互作用导致药物暴露不理想的情况，促使人们在药物研发过程中更早地开展旨在了解化合物与药物转运体之间相互作用的研究。虽然药物转运体可在肾脏或肝胆水平影响与人体剂量和暴露预测最为关键的药代动力学参数——清除率，但本文将聚焦于后者。
介绍了关于研究哪些转运体的指南概要以及当前可用工具的概述。还提供了关于何时对各种肝脏转运体进行研究的观点以及应促使早期研究的结构“警示”。
各个实验室以及通过合作团队在了解药物转运体在疾病、药物处置、药物相互作用和毒性方面的作用上已取得了巨大进展。现在似乎有必要对现有方法的价值进行系统分析并开展实验室间比较。利用物理化学性质指导未来筛选流程的新能力有望彻底改变早期药物研发的效率。
