Department of Pharmacology & Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona, USA.
Department of Physiology, College of Medicine, The University of Arizona, Tucson, Arizona, USA.
Clin Pharmacol Ther. 2023 Oct;114(4):780-794. doi: 10.1002/cpt.2984. Epub 2023 Jul 21.
The US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) guidances on small-molecule drug-drug interactions (DDIs), with input from the International Transporter Consortium (ITC), recommend the evaluation of nine drug transporters. Although other clinically relevant drug uptake and efflux transporters have been discussed in ITC white papers, they have been excluded from further recommendation by the ITC and are not included in current regulatory guidances. These include the ubiquitously expressed equilibrative nucleoside transporters (ENT) 1 and ENT2, which have been recognized by the ITC for their potential role in clinically relevant nucleoside analog drug interactions for patients with cancer. Although there is comparatively limited clinical evidence supporting their role in DDI risk or other adverse drug reactions (ADRs) compared with the nine highlighted transporters, several in vitro and in vivo studies have identified ENT interactions with non-nucleoside/non-nucleotide drugs, in addition to nucleoside/nucleotide analogs. Some noteworthy examples of compounds that interact with ENTs include cannabidiol and selected protein kinase inhibitors, as well as the nucleoside analogs remdesivir, EIDD-1931, gemcitabine, and fialuridine. Consequently, DDIs involving the ENTs may be responsible for therapeutic inefficacy or off-target toxicity. Evidence suggests that ENT1 and ENT2 should be considered as transporters potentially involved in clinically relevant DDIs and ADRs, thereby warranting further investigation and regulatory consideration.
美国食品和药物管理局（FDA）、欧洲药品管理局（EMA）和药品和医疗器械管理局（PMDA）的小分子药物相互作用（DDI）指南，在国际转运蛋白协会（ITC）的参与下，建议评估九种药物转运蛋白。尽管 ITC 白皮书中讨论了其他具有临床相关性的药物摄取和外排转运蛋白，但它们已被 ITC 排除在进一步建议之外，也未包含在当前的监管指南中。这些包括广泛表达的平衡核苷转运蛋白（ENT）1 和 ENT2，它们已被 ITC 认可，因其在癌症患者具有临床相关性的核苷类似物药物相互作用中具有潜在作用。尽管与突出的九种转运蛋白相比，支持它们在 DDI 风险或其他不良反应（ADR）中的作用的临床证据相对有限，但一些体外和体内研究已经确定了 ENT 与非核苷/非核苷酸药物的相互作用，除了核苷/核苷酸类似物。与 ENTs 相互作用的一些值得注意的化合物包括大麻二酚和选定的蛋白激酶抑制剂，以及核苷类似物瑞德西韦、EIDD-1931、吉西他滨和氟尿苷。因此，涉及 ENTs 的 DDI 可能导致治疗无效或脱靶毒性。有证据表明，ENT1 和 ENT2 应被视为可能涉及临床相关 DDI 和 ADR 的转运蛋白，从而需要进一步的研究和监管考虑。
