Drug–drug interactions are a major concern not only during clinical practice, but also in drug development. Due to limitations of in vitro–in vivo predictions of transporter-mediated drug–drug interactions, multiple clinical Phase I drug–drug interaction studies may become necessary for a new molecular entity to assess potential drug interaction liabilities. This is a resource-intensive process and exposes study participants, who frequently are healthy volunteers without benefit from study treatment, to the potential risks of a new drug in development. Therefore, there is currently a major interest in new approaches for better prediction of transporter-mediated drug–drug interactions. In particular, researchers in the field attempt to identify endogenous compounds as biomarkers for transporter function, such as hexadecanedioate, tetradecanedioate, coproporphyrins I and III, or glycochenodeoxycholate sulfate for hepatic uptake via organic anion transporting polypeptide 1B or N¹-methylnicotinamide for multidrug and toxin extrusion protein–mediated renal secretion. We summarize in this review the currently proposed biomarkers and potential limitations of the substances identified to date. Moreover, we suggest criteria based on current experiences, which may be used to assess the suitability of a biomarker for transporter function. Finally, further alternatives and supplemental approaches to classic drug–drug interaction studies are discussed.

中文翻译：

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体内评估转运蛋白功能的生物标志物

药物相互作用不仅在临床实践中而且在药物开发中都是主要关注的问题。由于转运蛋白介导的药物相互作用的体外-体内预测的局限性，对于新的分子实体评估潜在的药物相互作用负债，可能需要进行多个临床I期药物-药物相互作用研究。这是一个资源密集的过程，使研究参与者（他们经常是健康的志愿者，没有从研究治疗中受益）暴露于开发新药的潜在风险。因此，目前人们对更好地预测转运蛋白介导的药物相互作用的新方法非常感兴趣。特别是，该领域的研究人员试图鉴定内源性化合物作为转运蛋白功能的生物标记，例如十六烷二酸酯，十四烷二酸酯，^1-甲基烟酰胺用于多种药物和毒素挤出蛋白介导的肾脏分泌。我们在这篇综述中总结了目前提出的生物标志物和迄今为止鉴定出的物质的潜在局限性。此外，我们建议基于当前经验的标准，可用于评估生物标记物对转运蛋白功能的适用性。最后，讨论了经典药物相互作用研究的其他替代方法和补充方法。