Dose- and time-dependent manners of moxifloxacin induced liver injury by targeted metabolomics study

Moxifloxacin is the most widely prescribed antibiotics due to its excellent oral bioavailability and broad-spectrum antibacterial effect. Despite of its popularity, the rare and severe liver injury induced by moxifloxacin is a big concern that cannot be ignored in clinical practice. However, the early warning and related metabolic disturbances of moxifloxacin induced hepatoxicity were rarely reported. In this study, the dose- and time-dependent manners of moxifloxacin induced liver injury were investigated by a targeted metabolomics method. In dose-dependent experiment, three different dosages of moxifloxacin were administered to the rats, including 36 mg kg(-1) d(-1), 72 mg kg(-1) d(-1), and 108 mg kg(-1) d(-1). In time-dependent experiment, moxifloxacin was orally administered to the rats for 3, 7 or 14 consecutive days. Pathological analysis showed that moxifloxacin caused obvious transient hepatotoxicity, with the most serious liver injury occurred in the 7 days continuous administration group. The transient liver injury can be automatically restored over time. Serum levels of liver function related biochemical indicators, including ALT, AST, TBIL, alkaline phosphatase, superoxide dismutase, and malondialdehyde, were also measured for the evaluation of liver injury. However, these indicators can hardly be used for the early warning of hepatotoxicity caused by moxifloxacin due to their limited sensitivity and significant hysteresis. Targeted metabolomics study demonstrated that serum concentrations of fatty acyl carnitines, fatty acids and dehydroepiandrosterone can change dynamically with the severity of moxifloxacin related liver injury. The elevated serum levels of fatty acyl carnitine, fatty acid and dehydroepiandrosterone were promising in predicting the hepatotoxicity induced by moxifloxacin.

Automated summary

This study investigated the dose- and time-dependent manner of liver injury induced by moxifloxacin using a targeted metabolomics method. The results showed that moxifloxacin caused transient hepatotoxicity, with the most severe liver injury occurring after 7 days of continuous administration. Serum concentrations of fatty acyl carnitines, fatty acids, and dehydroepiandrosterone changed dynamically with the severity of moxifloxacin-related liver injury, suggesting their potential as biomarkers for predicting hepatotoxicity.