ABSTRACT
Introduction: The study objectives were to estimate plasma flunixin (FLU) pharmacokinetic parameters and milk depletion profiles for FLU and its metabolite (5-hydroxy flunixin; 5-OH) after subcutaneous (SC) and intravenous (IV) administration of single and multiple flunixin meglumine (FM) doses to non-lactating (nulliparous and pregnant does) and lactating dairy goats. Analytical methods (ELISA and UPLC-MS/MS) for quantifying plasma FLU concentrations were compared. The final objective was to use regulatory (FDA and EMA) methods to estimate milk withdrawal intervals following extra-label drug use in goats. Methods: FM was administered IV and SC to commercial dairy goats at 1.1 mg/kg for single and multiple doses. Plasma and milk samples were analyzed for FLU and 5-OH via UPLC-MS/MS. Plasma samples were also analyzed for FLU concentrations via ELISA. Using statistical approaches recommended by regulatory agencies, milk withdrawal intervals were estimated following FM extra-label use. Results: Following IV administration of a single FM dose, clearances were 127, 199, and 365 ml/kg/h for non-lactating (NL) pregnant does, NL nulliparous does, and lactating dairy does, respectively. Following multiple SC doses, clearance/F was 199 ml/kg/h for lactating does. After IV administration of a single FM dose, terminal elimination half-lives were 4.08, 2.87, and 3.77 h for NL pregnant does, NL nulliparous does, and lactating dairy does, respectively. After multiple SC doses, the terminal elimination half-life was 3.03 h for lactating dairy does. No significant differences were noted for samples analyzed by UPLC-MS/MS or ELISA. Milk withdrawal intervals ranged from 36 to 60 h depending on the regulatory statistical method and dosage regimen. Conclusions: Subcutaneous administration of FM to goats results in similar plasma pharmacokinetic parameters as IV administration. ELISA analysis is an alternative method to UPLC-MS/MS for quantifying FLU concentrations in caprine plasma samples. Following FM extra-label administration to dairy goats, clinicians could consider 36-60 h milk withdrawal intervals.
ABSTRACT
Six nonlactating and six lactating adult female goats received a single subcutaneous injection of ceftiofur crystalline free acid (CCFA) at a dosage of 6.6 mg/kg. Blood samples were collected from the jugular vein before and at multiple time points after CCFA administration. Milk samples were collected twice daily. Concentrations of ceftiofur and desfuroylceftiofur-related metabolites were measured using high-performance liquid chromatography. Data were analyzed using compartmental and noncompartmental approaches. The pharmacokinetics of CCFA in the domestic goat was best described by a one compartment model. Mean (±SD) pharmacokinetic parameters were as follows for the nonlactating goats: area under the concentration time curve(0-∞) (159 h·µg/mL ± 19), maximum observed serum concentration (2.3 µg/mL ± 1.1), time of maximal observed serum concentration (26.7 h ± 16.5) and terminal elimination half life (36.9 h; harmonic). For the lactating goats, the pharmacokinetic parameters were as follows: area under the concentration time curve(0-∞) (156 h·µg/mL ± 14), maximum observed serum concentration (1.5 µg/mL ± 0.4), time of maximal observed serum concentration (46 h ± 15.9) and terminal elimination half life (37.3 h; harmonic). Ceftiofur and desfuroylceftiofur-related metabolites were only detectable in one milk sample at 36 h following treatment. There were no significant differences in the pharmacokinetic parameter between the nonlactating and lactating goats.
