Mechanism and marker of voriconazole–induced liver injury: insights from a quantitative systems toxicology approach

Liver injury severely limits the clinical use of voriconazole. Clarifying the mechanism and markers of voriconazole–induced liver injury is of great significance. In this study, a quantitative systems toxicology model of voriconazole–induced liver injury was constructed through integrating the mechanism–based hepatoxic parameters generated from in vitro assays into a self–built physiologically based pharmacokinetic model. The hepatotoxic substances, main mechanism, dose correlation and markers of voriconazole–induced liver injury were determined according to liver injury incidence of simulated populations. The voriconazole–treated mice, voriconazole or voriconazole N–oxide (VNO)–treated HepG2 were used to validate the relationship of liver injury with oxidative stress and VNO. The results demonstrated that the incidence of voriconazole–induced liver injury was 17.9 %, which was dose–dependent. VNO–induced oxidative stress contributed most to liver injury, which was manifested by reactive oxygen species (ROS) accumulation and antioxidant enzymes inhibition. Liver ROS/reactive nitrogen species baseline clearance V_max and antioxidant enzymes activities were negatively correlated to plasma liver function indicators elevation and liver adenosine triphosphate loss. We concluded that VNO–induced oxidative stress was the main cause of voriconazole–induced liver injury, and basic antioxidant capability indicators might be potential markers. This study may provide new insights for mechanism understanding and early warning of voriconazole–induced liver injury.