Metabolomics analysis of plasma reveals voriconazole-induced hepatotoxicity is associated with oxidative stress

Abstract Voriconazole is one of the most frequently used antifungal drugs for the initial treatment of invasive aspergillosis, but liver-related adverse events occur frequently and usually lead to drug discontinuation. Moreover, the mechanism of voriconazole-induced hepatotoxicity remains unsettled. A holistic understanding of its mechanism is critical to prevent liver-related adverse events. Metabolomics has been demonstrated to be a helpful strategy for investigating drug-induced toxicity. This study aimed to utilize human plasma samples to investigate the mechanism of voriconazole-induced hepatotoxicity through a metabolomics approach. Patients that were administered voriconazole were classified into a voriconazole-induced hepatotoxicity group and control group (n = 65, 18% hepatotoxicity). Plasma samples were analyzed by targeted metabolomics using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. The obtained peak areas for each metabolite were utilized for correlation analysis, fold change evaluation, and univariate statistical tests to identify metabolites associated with voriconazole-induced hepatotoxicity. This study showed a significantly lower glutamine-to-glutamate ratio (p = .04) and a higher β-N-acetylglucosamine (p = .003) in the voriconazole-induced hepatotoxicity group, implying the presence of oxidative stress. Other significant metabolites also indicated several adaptive responses to oxidative stress in patients with voriconazole-induced toxicity, including cell repair, energy production, and alteration to bile acid hemostasis. Furthermore, a metabolite panel consisting of α-ketoglutarate, glycocholate, and β-N-acetylglucosamine demonstrated better performance for detecting voriconazole-induced hepatotoxicity than conventional liver function tests. These metabolomics findings reveal that voriconazole-induced hepatotoxicity is associated with oxidative stress.