Pharmacokinetics of flunixin in mature heifers following multiple intravenous administration

The pharmacokinetics of flunixin meglumine was determined after its multiple (altogether 4 doses at 24-hours intervals) intravenous administration at a dose of 2.2 mg/kg body weight in six mature clinically healthy heifers. Plasma flunixin and its metabolite 5-hydroxyflunixin concentrations were analyzed with high-pressure liquid chromatography using an assay with a lower limit detection of 0.03 microg/ml for both substances. Plasma concentrations versus time curves were described by a two compartment open model. Mean plasma flunixin concentrations were similar on day 1 and 4, and than rapidly decreased (within 2 hours) from initial concentrations higher than 10 microg/ml to the concentrations lower than 1 microg/ml. The distribution phase of flunixin was short (t0.5 alpha = 0.29 +/- 0.16 and 0.18 +/- 0.04 on day 1 and 4, respectively) and the elimination phase was more prolonged (t0.5 beta = 3.30 +/- 0.60 and 3.26 +/- 0.22 on day 1 and 4, respectively). The mean residence time of flunixin was similar on day 1 (1.83 +/- 0.83) and 4 (1.88 +/- 0.46), and for 5-hydroxyflunixin this parameter was insignificantly (P > 0.05) higher on day 1 (5.49 +/- 2.22) as compared to that found on day 4 (3.99 +/- 2.17). The clearance of flunixin was similar on both examined days (0.23 +/- 0.12 on day 1 and 0.31 +/- 0.15 on day 4), and for 5-hydroxyflunixin was insignificantly (P > 0.05) lower on day 1 (2.37 +/- 1.21) as compared to that determined on day 4 (3.23 +/- 1.06). Our data indicate that multiple administration of flunixin did not alter significantly the parent drug and its metabolite concentrations in plasma, however may cause some small changes in pharmacokinetic parameters.