Toxicokinetics of Levofloxacin in Beagle Dog Plasma Based on HPLC-MS/MS

OBJECTIVE To establish a rapid and sensitive HPLC-MS/MS quantitative detection method for the determination of levofloxacin in Beagle dog plasma, and to investigate the toxicokinetics of levofloxacin in Beagle dogs using this method, while also evaluating its toxicity through a long-term administration toxicity test.

METHODS Established an HPLC-MS/MS method using norfloxacin as the internal standard; Beagle dogs were randomly divided into control group and low, medium, high dose groups of levofloxacin hydrochloride, with 10 dogs in each group. The administration was via oral gavage, with the control group receiving purified water once daily for 4 weeks of dosing followed by a 4-week recovery period. Plasma samples were collected from Beagle dogs before and after the first and last doses for analysis. The toxicokinetic behavior of levofloxacin in animals was assessed using the DAS 3.3 non-compartmental model. General observations of animal condition, as well as measurements of body temperature, electrocardiography, ophthalmology, hematology, serum biochemistry, and urine analysis, were conducted. At the end of the dosing period and recovery period, necropsy and histopathological examination of tissues were performed.

RESULTS The main toxicokinetic parameters dose correlation, sex exposure differences, and the effects of repeated administration were investigated. The study found that AUC_(0-24) and C_max showed a certain dose-dependent increase. The significantly increased AUC_(0-24) observed in female animals of the high-dose group may be attributed to sex-based differences in metabolizing enzyme activity. After a four-week repeated administration, there was no significantly accumulation of levofloxacin at each dose. The long-term toxicity study revealed significant gastrointestinal irritation reactions in animals from the medium and high dose groups. Urine analysis results indicated a potential mild impact of the drug on renal function. Hematological examination results suggested a potential influence of the drug on coagulation function. However, these symptoms disappeared during the recovery period.

CONCLUSION This method is simple, accurate, and exhibits good repeatability, making it suitable for the determination of levofloxacin concentrations in Beagle dog plasma and for conducting toxicokinetic studies. It provides valuable reference data for toxicity evaluation in toxicological experiments.