Distribution of Flunixin Residues in Muscles of Dairy Cattle Dosed with Lipopolysaccharide or Saline and Treated with Flunixin by Intravenous or Intramuscular Injection

Abstract

Twenty dairy cows received flunixin meglumine at 2.2 mg/kg bw, administered once daily by either the intravenous (IV) or intramuscular (IM) route for three consecutive days with either intravenous normal saline (NS) or lipopolysaccharide (LPS) providing a balanced design with five animals per group. Cows were sacrificed after a 4 day withdrawal period, and 13 muscle types were collected and assayed for flunixin by LC-MS/MS. After elimination of sample outliers, the main effects of route of administration (IV or IM), treatment (NS or LPS), and tissue type significantly (P < 0.05) affected flunixin residues, with no interaction (P > 0.05). Intramuscular (nonlabel) flunixin administration produced greater (P < 0.05) flunixin residues in muscle than the IV (label) administration, whereas LPS resulted in lower flunixin levels. Differences among the tissue levels indicate it is necessary to specify the tissue to be used for any monitoring of drug levels for consumer protection.

Using simulations to explore the potential effect of disease and inflammation on the frequency of violative flunixin residues in cattle

“…It also is worthwhile mentioning the observed trend toward lower muscle flunixin concentrations in LPS-treated versus control dairy cattle as reported by investigators from that same laboratory for cattle administered the drug via IV injection (Shelver et al, 2016).…”

“…Consequently, the estimates of plasma flunixin AUC reported by Smith et al (2015) were derived from plasma data spanning the entire FDA-assigned withdrawal period, while the plasma flunixin AUC estimates reported by Kissell et al (2015) only represented a quarter of the FDA-assigned withdrawal period. Thus, when considered together, these data suggest that large differences in plasma AUC observed within hours of flunixin administration reported by Kissell et al (2015) may not be associated with higher systemic blood concentrations or tissue residue levels occurring at the FDAassigned withdrawal period (Shelver et al, 2016;Smith et al, 2015).…”

“…We selected a simple and straightforward approach that utilizes the data submitted to the FDA, in combination with Monte Carlo simulations, to interrogate the effect of changing tissue depletion kinetics on the frequency of violative residues. In doing so, we avoided confounding approaches reported by other studies, namely the use of an analytical method other than the official analytical method (Kissell et al, 2015; Shelver et al, 2016; Smith et al, 2015) and calculation of a “new” withdrawal period to assess the human food safety risk (Chou et al, 2022; Li et al, 2019).…”

Role of ABCG2 in Secretion into Milk of the Anti-Inflammatory Flunixin and Its Main Metabolite: In Vitro-In Vivo Correlation in Mice and Cows

“…In fact, 5OH-FLU levels are higher than FLU levels in cow milk (Feely et al, 2002), probably due in part to their different physicochemical properties and the extensive liver metabolism of FLU. Nevertheless, some studies have shown that alteration of the dose or route of administration, or the presence of disease processes, could affect the presence of violative residues even after withdrawal periods are finished (Kissell et al, 2015;Smith et al, 2015;Shelver et al, 2016).…”

Development of an indirect competitive enzyme-linked immunosorbent assay for detecting flunixin and 5-hydroxyflunixin residues in bovine muscle and milk

“…The analgesic and antipyretic effects usually occur 1-2 h after treatment, and the maximum effect is maintained for between 2 and 16 h (Aké-López, Segura-Correa, & Quintal-Franco, 2005;Levionnois et al, 2018). Since October 2004, flunixin has been approved by the Food and Drug Administration for lactation and has been widely used in the United States, France, Switzerland, Germany and the United Kingdom (Shelver, Schneider, & Smith, 2016). In addition, flunixin has been approved by the Chinese Ministry of Agriculture for veterinary use in animal husbandry since 2007.…”