Drug-induced liver injury (DILI) continues to be a major cause of drug attrition and restrictive labeling. Given the importance of farnesoid X receptor (FXR) in bile acid homeostasis, drug-related FXR antagonism may be an important mechanism of DILI. However, a comprehensive assessment of this phenomenon broadly in the context of DILI is lacking. As such, we used an orthogonal approach comprising a FXR target gene assay in primary human hepatocytes and a commercially available FXR reporter assay to investigate the potential FXR antagonistic effects of an extensive test set of 159 compounds with and without association with clinical DILI. Data were omitted from analysis based on the presence of cytotoxicity to minimize false positive assay signals and other complications in data interpretation. Based on the experimental approaches employed and corresponding data, the prevalence of FXR antagonism was relatively low across this broad DILI test set, with 16–24% prevalence based on individual assay results or combined signals in both assays. Moreover, FXR antagonism was not highly predictive for identifying clinically relevant hepatotoxicants retrospectively, where FXR antagonist classification alone had minimal to moderate predictive value as represented by positive and negative likelihood ratios of 2.24–3.84 and 0.72–0.85, respectively. The predictivity did not increase significantly when considering only compounds with high clinical exposure (maximal or efficacious plasma exposures > 1.0 μM). In contrast, modest gains in predictive value of FXR antagonism were observed considering compounds that also inhibit bile salt export pump. In addition, we have identified novel FXR antagonistic effects of well-studied hepatotoxic drugs, including bosentan, tolcapone and ritonavir. In conclusion, this work represents a comprehensive evaluation of FXR antagonism in the context of DILI, including its overall predictivity and challenges associated with detecting this phenomenon in vitro.

药物性肝损伤（DILI）仍然是药物消耗和限制性标记的主要原因。鉴于法尼醇X受体（FXR）在胆汁酸稳态中的重要性，与药物相关的FXR拮抗作用可能是DILI的重要机制。然而，在DILI的背景下，缺乏对这一现象的广泛评估。因此，我们使用了一种正交方法，该方法包括在原代人肝细胞中进行FXR靶基因测定和通过商业途径获得的FXR报告子测定法，以研究159种化合物的广泛测试组在与临床DILI相关联和不与临床DILI相关联方面的潜在FXR拮抗作用。基于细胞毒性的存在从分析中省略数据，以最大程度地减少假阳性测定信号和数据解释中的其他复杂性。根据所采用的实验方法和相应的数据，在这一广泛的DILI测试集中，FXR拮抗作用的发生率相对较低，根据单独的测定结果或两种测定中的组合信号，其发生率为16-24％。此外，FXR拮抗作用对于回顾性鉴定临床上相关的肝毒剂的预测作用不是很高，因为仅FXR拮抗剂分类具有最小至中等的预测值，分别由阳性和阴性似然比分别为2.24-3.84和0.72-0.85表示。当仅考虑具有高临床暴露量（最大或有效血浆暴露量> 1.0μM）的化合物时，可预测性并未显着增加。相反，考虑到还抑制胆汁盐输出泵的化合物，观察到FXR拮抗作用的预测值有适度的提高。此外，我们已经确定了经过深入研究的肝毒性药物（包括波生坦，托卡朋和利托那韦）的新型FXR拮抗作用。总之，这项工作代表了DILI背景下对FXR拮抗作用的全面评估，包括其总体预测性以及与在体外检测到该现象相关的挑战。