Pharmacokinetic Parameters and Estimated Milk Withdrawal Intervals for Domestic Goats (Capra Aegagrus Hircus) After Administration of Single and Multiple Intravenous and Subcutaneous Doses of Flunixin Meglumine

Joe S Smith; Tara L Marmulak; John A Angelos; Zhoumeng Lin; Joan D Rowe; Jan L Carlson; Weilin L Shelver; Elizabeth A Lee; Lisa A Tell

doi:10.3389/fvets.2020.00213

Pharmacokinetic Parameters and Estimated Milk Withdrawal Intervals for Domestic Goats (Capra Aegagrus Hircus) After Administration of Single and Multiple Intravenous and Subcutaneous Doses of Flunixin Meglumine

Front Vet Sci. 2020 May 19:7:213. doi: 10.3389/fvets.2020.00213. eCollection 2020.

Authors

Joe S Smith¹, Tara L Marmulak², John A Angelos², Zhoumeng Lin³, Joan D Rowe⁴, Jan L Carlson⁵, Weilin L Shelver⁶, Elizabeth A Lee², Lisa A Tell²

Affiliations

¹ School of Veterinary Medicine, William R. Pritchard Veterinary Medical Teaching Hospital (VMTH), University of California, Davis, Davis, CA, United States.
² Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
³ Department of Anatomy and Physiology, Institute of Computational Comparative Medicine (ICCM), College of Veterinary Medicine, Kansas State University, Manhattan, KS, United States.
⁴ Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
⁵ Department of Animal Science, College of Agricultural and Environmental Sciences, University of California, Davis, Davis, CA, United States.
⁶ USDA-ARS Biosciences Research Laboratory, Fargo, ND, United States.

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.

Keywords: flunixin meglumine; goat; milk; pharmacokinetics; subcutaneous; withdrawal interval.