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.