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.
Highlights
IntroductionThe study objectives were to estimate plasma flunixin (FLU) pharmacokinetic parameters and milk depletion profiles for FLU and its metabolite (5-hydroxy flunixin; 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
The study objectives were to estimate plasma flunixin (FLU) pharmacokinetic parameters and milk depletion profiles for FLU and its metabolite (5-hydroxy flunixin; 5-Hydroxy flunixin (5-OH)) after subcutaneous (SC) and intravenous (IV) administration of single and multiple flunixin meglumine (FM) doses to non-lactating and lactating dairy goats
FLU concentrations quantified using an Enzyme-Linked Immunoassay (ELISA) method were compared to those using Ultra-performance liquid chromatography (UPLC)-MS/MS to determine if analytical method choice would result in similar FLU concentrations
Summary
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. Drug residue problems are not limited to meat, as FLU metabolite residues found in bovine milk are some of the Abbreviations: Cmax, Maximum concentration (observed); CV, Coefficient of variation; CVMP, Committee for Veterinary Products for Medical Use; ELISA, Enzyme-linked immunosorbent assay; EMA, European Medicines Agency; FDA, Food and Drug Administration (USA); FLU, Flunixin; FM, Flunixin meglumine; IV, Intravenous; LOD, Limit of detection; LOQ, Limit of quantification; MD, Multiple dose; LC-MS/MS, Liquid chromatography mass spectrometry; NL, Non-lactating; NSAIDS, Non-steroidal anti-inflammatory drugs; PD, Pharmacodynamic(s); PK, Pharmacokinetic(s); SC, Subcutaneous; SD, Single dose; T1/2λz, Terminal elimination half-life; Tmax, Time to maximum concentration (observed); UPLC, Ultra-performance liquid chromatography; USA, United States of America; USDA, United States Department of Agriculture; 5-OH, 5-Hydroxy flunixin
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