School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
Int J Antimicrob Agents. 2024 Jan;63(1):107028. doi: 10.1016/j.ijantimicag.2023.107028. Epub 2023 Nov 4.
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.
伏立康唑相关性肝毒性是一种常见的情况，通常表现为肝酶升高，并可能导致药物停用。需要仔细监测伏立康唑相关性肝毒性，但目前尚无该疾病的特定血浆生物标志物。代谢组学已成为研究与药物毒性相关的生物标志物的一种很有前途的技术。本研究旨在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性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被分为肝毒性组（18 例）或对照组（153 例）。使用超高效液相色谱-质谱联用分析血浆样本。比较两组的代谢物浓度。使用逻辑回归生成的接收者操作特征（AUROC）曲线下面积来关联这七种代谢物的浓度与伏立康唑谷浓度和常规肝功能测试。与对照组相比，肝毒性组的甘氨胆酸和α-酮戊二酸水平显著升高（经错误发现率校正后 P < 0.001 和 P = 0.024）。代谢物甘氨胆酸（AUROC = 0.795）和α-酮戊二酸（AUROC = 0.696）的性能优于伏立康唑谷浓度（AUROC = 0.555），接近碱性磷酸酶（AUROC = 0.876）和总胆红素（AUROC = 0.815）的性能。甘氨胆酸联合伏立康唑谷浓度的面板（AUROC = 0.827）在预测肝毒性方面显著提高了伏立康唑谷浓度单独预测的性能。总之，甘氨胆酸与伏立康唑谷浓度相结合的面板在识别伏立康唑相关性肝毒性方面具有很大的潜力。
