The Competitive Counterflow Assay for Identifying Drugs Transported by Solute Carriers: Principle, Applications, Challenges/Limits, and Perspectives.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Olivier Fardel, Amélie Moreau, Jennifer Carteret, Claire Denizot, Marc Le Vée, Yannick Parmentier
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引用次数: 0

Abstract

The identification of substrates for solute carriers (SLCs) handling drugs is an important challenge, owing to the major implication of these plasma membrane transporters in pharmacokinetics and drug-drug interactions. In this context, the competitive counterflow (CCF) assay has been proposed as a practical and less expensive approach than the reference functional uptake assays for discriminating SLC substrates and non-substrates. The present article was designed to summarize and discuss key-findings about the CCF assay, including its principle, applications, challenges and limits, and perspectives. The CCF assay is based on the decrease of the steady-state accumulation of a tracer substrate in SLC-positive cells, caused by candidate substrates. Reviewed data highlight the fact that the CCF assay has been used to identify substrates and non-substrates for organic cation transporters (OCTs), organic anion transporters (OATs), and organic anion transporting polypeptides (OATPs). The performance values of the CCF assay, calculated from available CCF study data compared with reference functional uptake assay data, are, however, rather mitigated, indicating that the predictability of the CCF method for assessing SLC-mediated transportability of drugs is currently not optimal. Further studies, notably aimed at standardizing the CCF assay and developing CCF-based high-throughput approaches, are therefore required in order to fully precise the interest and relevance of the CCF assay for identifying substrates and non-substrates of SLCs.

Abstract Image

鉴定溶质载体运输药物的竞争性逆流试验:原理、应用、挑战/限制和展望。
由于溶质载体(SLC)在药代动力学和药物间相互作用中的重要作用,鉴定这些质膜转运体处理药物的底物是一项重要挑战。在这种情况下,有人提出了竞争性逆流(CCF)测定法,它是一种实用且成本低于参考功能摄取测定法的方法,可用于区分 SLC 底物和非底物。本文旨在总结和讨论有关 CCF 检测法的主要发现,包括其原理、应用、挑战和限制以及展望。CCF 检测法基于候选底物导致的示踪底物在 SLC 阳性细胞中稳态积累的减少。回顾数据显示,CCF 试验已被用于鉴定有机阳离子转运体(OCTs)、有机阴离子转运体(OATs)和有机阴离子转运多肽(OATPs)的底物和非底物。不过,根据现有的 CCF 研究数据与参考功能摄取测定数据比较计算得出的 CCF 测定性能值相当低,这表明 CCF 方法在评估 SLC 介导的药物转运能力方面的可预测性目前并不理想。因此还需要进一步研究,特别是旨在标准化CCF测定和开发基于CCF的高通量方法的研究,以充分明确CCF测定对鉴定SLC底物和非底物的意义和相关性。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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