Abstract：
In recent years, various endogenous compounds have been proposed as putative biomarkers for the hepatic uptake transporters OATP1B1 and OATP1B3 that have the potential to predict transporter-mediated drug-drug interactions (DDIs). However, these compounds have often been identified from top-down strategies and have not been fully utilized as a substitute for traditional DDI studies. In an attempt to eliminate observer bias in biomarker selection, we applied a bottom-up, untargeted metabolomics screening approach in mice and found that plasma levels of the conjugated bile acid chenodeoxycholate-24-glucuronide (CDCA-24G) are particularly sensitive to deletion of the orthologous murine transporter Oatp1b2 (31-fold increase vs. wild type) or the entire Oatp1a/1b(-/-)cluster (83-fold increased), whereas the humanized transgenic overexpression of hepatic OATP1B1 or OATP1B3 resulted in the partial restoration of transport function. Validation studies with the OATP1B1/OATP1B3 inhibitors rifampin and paclitaxel in vitro as well as in mice and human subjects confirmed that CDCA-24G is a sensitive and rapid response biomarker to dose-dependent transporter inhibition. Collectively, our study confirmed the ability of CDCA-24G to serve as a sensitive and selective endogenous biomarker of OATP1B-type transport function and suggests a template for the future development of biomarkers for other clinically important xenobiotic transporters.
摘要：
近年来,已提出多种内源性化合物作为肝摄取转运蛋白OATP1B1和OATP1B3的推定生物标志物,它们具有预测转运蛋白介导的药物-药物相互作用(DDI)的潜力.然而,这些化合物通常是从自上而下的策略中鉴定出来的,并且尚未完全用作传统DDI研究的替代品.为了消除生物标志物选择中的观察者偏见，我们应用了自下而上的方法，小鼠的非靶向代谢组学筛选方法，发现结合胆汁酸鹅去氧胆酸-24-葡糖苷酸（CDCA-24G）的血浆水平对直系同源鼠转运蛋白Oatp1b2的缺失特别敏感（增加31倍与野生型）或整个Oatp1a/1b（-/-）簇（增加83倍），而肝OATP1B1或OATP1B3的人源化转基因过表达导致转运功能的部分恢复。在体外以及在小鼠和人类受试者中使用OATP1B1/OATP1B3抑制剂利福平和紫杉醇的验证研究证实，CDCA-24G是对剂量依赖性转运蛋白抑制的敏感且快速反应的生物标志物。总的来说，我们的研究证实了CDCA-24G作为OATP1B型转运功能的敏感和选择性内源性生物标志物的能力,并为未来开发其他临床重要的异种生物转运蛋白的生物标志物提供了模板.
