Abstract：
Voriconazole-associated hepatotoxicity is a common condition that generally manifests as elevated liver enzymes and can lead to drug discontinuation. Careful monitoring of voriconazole-associated hepatotoxicity is needed but there are no specific plasma biomarkers for this condition. Metabolomics has emerged as a promising technique for investigating biomarkers associated with drug-induced toxicity. The aim of this study was to use targeted metabolomics to evaluate seven endogenous metabolites as potential biomarkers of voriconazole-associated hepatotoxicity. Patients undergoing therapeutic drug monitoring of voriconazole were classified into a hepatotoxicity group (18 patients) or a control group (153 patients). Plasma samples were analysed using ultra-high-performance liquid chromatography coupled to mass spectrometry. Metabolite concentrations in the two groups were compared. Areas under the receiver operating characteristic (AUROC) curves generated from logistic regressions were used to correlate the concentrations of these seven metabolites with voriconazole trough concentrations and conventional liver biochemistry tests. Glycocholate and α-ketoglutarate levels were significantly higher in the hepatotoxicity group compared with the control group (false discovery rate-corrected P < 0.001 and P = 0.024, respectively). The metabolites glycocholate (AUROC = 0.795) and α-ketoglutarate (AUROC = 0.696) outperformed voriconazole trough concentrations (AUROC = 0.555) and approached the performance of alkaline phosphatase (AUROC = 0.876) and total bilirubin (AUROC = 0.815). A panel of glycocholate combined with voriconazole trough concentrations (AUROC = 0.827) substantially improved the performance of voriconazole trough concentrations alone in predicting hepatotoxicity. In conclusion, the panel integrating glycocholate with voriconazole trough concentrations has great potential for identifying voriconazole-associated hepatotoxicity.
摘要：
伏立康唑相关的肝毒性是一种常见病，通常表现为肝酶升高，并可导致药物停药。需要仔细监测伏立康唑相关的肝毒性，但没有针对这种情况的特定血浆生物标志物。代谢组学已成为研究与药物诱导毒性相关的生物标志物的有前途的技术。这项研究的目的是使用靶向代谢组学来评估七种内源性代谢物作为伏立康唑相关肝毒性的潜在生物标志物。接受伏立康唑治疗药物监测的患者分为肝毒性组（18例）或对照组（153例）。使用超高效液相色谱和质谱联用分析血浆样品。比较两组的代谢物浓度。由逻辑回归产生的受试者工作特征（AUROC）曲线下的面积用于将这7种代谢物的浓度与伏立康唑谷浓度和常规肝脏生物化学测试相关联。与对照组相比，肝毒性组的胆酸和α-酮戊二酸水平显着升高（假发现率校正P<0.001和P=0.024）。代谢产物糖胆酸（AUROC=0.795）和α-酮戊二酸（AUROC=0.696）优于伏立康唑谷浓度（AUROC=0.555），并接近碱性磷酸酶（AUROC=0.876）和总胆红素（AUROC=0.815）的表现。一组糖胆酸盐联合伏立康唑谷浓度（AUROC=0.827）显着提高了伏立康唑谷浓度单独预测肝毒性的性能。总之,整合甘氨胆酸盐和伏立康唑谷浓度的小组在鉴定伏立康唑相关肝毒性方面具有巨大潜力.
