Occurrence of flunixin residues in bovine milk samples from the USA.

5-Hydroxy-flunixin concentrations in milk samples were quantified by two commercially available screening assays--CHARM® and enzyme-linked immunoabsorbant assay (ELISA)--to determine whether any concentrations could be detected above the tolerance limit of 2 ng g⁻¹ from different regions in the United States. Milk samples came from large tanker trucks hauling milk to processing plants, and had already been screened for antibiotics. Positive results for flunixin residues based on a screening assay were confirmed by ultra-HPLC with mass spectrometric detection. Of the 500 milk samples analysed in this study, one sample was found to have a 5-hydroxy-flunixin concentration greater than the tolerance limit. The results of this study indicate that flunixin residues in milk are possible. Regulatory agencies should be aware that such residues can occur, and should consider incorporating or expanding flunixin screening tests as part of routine drug monitoring in milk. Larger studies are needed to determine the true prevalence of flunixin residues in milk from other regions in the United States as well as different countries.

Plasma pharmacokinetics and milk residues of flunixin and 5-hydroxy flunixin following different routes of administration in dairy cattle.

The objective of this study was to determine if the plasma pharmacokinetics and milk elimination of flunixin (FLU) and 5-hydroxy flunixin (5OH) differ following intramuscular and subcutaneous injection of FLU compared with intravenous injection. Twelve lactating Holstein cows were used in a randomized crossover design study. Cows were organized into 2 groups based on milk production (<20 or >30 kg of milk/d). All cattle were administered 2 doses of 1.1mg of FLU/kg at 12-h intervals by intravenous, intramuscular, and subcutaneous injections. The washout period between routes of administration was 7d. Blood samples were collected from the jugular vein before FLU administration and at various time points up to 36 h after the first dose of FLU. Composite milk samples were collected before FLU administration and twice daily for 5d after the first dose of FLU. Samples were analyzed by ultra-HPLC with mass spectrometric detection. For FLU plasma samples, a difference in terminal half-life was observed among routes of administration. Harmonic mean terminal half-lives for FLU were 3.42, 4.48, and 5.39 h for intravenous, intramuscular, and subcutaneous injection, respectively. The mean bioavailability following intramuscular and subcutaneous dosing was 84.5 and 104.2%, respectively. The decrease in 5OH milk concentration versus time after last dose was analyzed with the nonlinear mixed effects modeling approach and indicated that both the route of administration and rate of milk production were significant covariates. The number of milk samples greater than the tolerance limit for each route of administration was also compared at each time point for statistical significance. Forty-eight hours after the first dose, 5OH milk concentrations were undetectable in all intravenously injected cows; however, one intramuscularly injected and one subcutaneously injected cow had measurable concentrations. These cows had 5OH concentrations above the tolerance limit at the 36-h withdrawal time. The high number of FLU residues identified in cull dairy cows by the United States Department of Agriculture Food Safety Inspection Service is likely related to administration of the drug by an unapproved route. Cattle that received FLU by the approved (intravenous) route consistently eliminated the drug before the approved withdrawal times; however, residues can persist beyond these approved times following intramuscular or subcutaneous administration. Cows producing less than 20 kg of milk/d had altered FLU milk clearance, which may also contribute to violative FLU residues.