Tissue distribution and residue depletion of difloxacin in crucian carp ( Carassius carassius ) after multiple oral administration

Although difloxacin is not listed by Codex or the US FDA, China and some countries in Asia have approved this drug for use in aquaculture. Additionally, both China and EMA have adopted the same maximum residue limit (MRL) for difloxacin in muscle plus skin at 0.3 mu g/g. However, a withdrawal period has not been established for difloxacin in aquaculture. Therefore, the primary goal of this investigation was to evaluate the tissue distribution and residue depletion of difloxacin in crucian carp (Carassius carassius) kept in freshwater at a temperature of 21 +/- 1 degrees C, with the aim of determining an appropriate withdrawal period. This investigation entailed the oral administration of difloxacin via gavage, employing a daily dosage of 20 mg/kg body weight (BW) over a consecutive three-day regimen. Diverse samples, including plasma, bile, skin-on-muscle, liver, kidney, intestine, and gill, were collected at predetermined time intervals after the final administration. The quantification of difloxacin concentrations in all collected samples was carried out utilizing a high-performance liquid chromatography (HPLC) method. Difloxacin exhibited extensive distribution within crucian carp, with detectable presence in all examined tissues. The highest average concentration was notably observed in the bile with a Cmax of 14.359 mu g/mL. Remarkably, even on the 15th day (360 h) following the final dosing, traces of difloxacin residues remained detectable in all collected samples. Pharmacokinetic parameters, determined through the noncompartmental model, unveiled diverse elimination half-lives (t1/2 lambda zs) for difloxacin across distinct samples, ranging from rapid to slow: plasma (9.46 days), skin-on muscle (10.15 days), liver (10.36 days), bile (13.05 days), intestine (20.94 days), kidney (22.12 days), and gill (29.56 days). Taking into consideration the MRL, a withdrawal period of 32 days was definitively determined, derived from the upper limit of the one-sided 95% confidence interval. When converted to the unit of degrees C-day, the withdrawal period was determined to be 660.