DETERMINATION OF PHARMACOKINETICS AND PHARMACODYNAMICS OF FLUNIXIN INCALVES BY USE OF PHARMACOKINETIC-PHARMACODYNAMIC MODELING

Pharmacokinetic and pharmacodynamic variables of flunixin were studied in calves after IV administration of the drug at a dose rate of 2.2 m g/kg of body weight. The anti-inflammatory properties of flunixin were investigated, using a model of acute inflammation; this involved surg ically implanting tissue cages at subcutaneous sites and stimulating t he tissue cage granulation tissue by intracavitary injection of carrag eenan. The actions of flunixin on exudate concentrations of several su bstances related to the inflammatory process, including proteases (met alloprotease [active and total] and cysteine and serine proteases), en zymes (lactate dehydrogenase, acid phosphatase, and beta-glucuronidase [beta-glu]), eicosanoid (prostaglandin E(2) [PGE(2)], leukotriene B-4 , and serum thromboxane B-2 [TXB(2)]) concentrations, and bradykinin ( BK)-induced edema, were investigated. Flunixin had a long elimination half-life-6.87 +/- 0.49 hours-and volume of distribution was 2.11 +/- 0.37 L/kg, indicating extensive distribution of the drug in the body. Body clearance was 0.20 +/- 0.03 L/kg/h. Flunixin exerted inhibitory e ffects on serum TXB(2) and exudate PGE(2) concentrations, beta-glu act ivity, and BK-induced swelling. Other enzymes and inflammatory mediato rs were not significantly affected. Pharmacokinetic/pharmacodynamic mo deling of the data revealed similar mean concentration producing 50% o f the maximal effect values for inhibition of exudate PGE(2) and beta- glu and of BK-induced swelling (0.070 +/- 0.006, 0.064 +/- 0.040, and 0.061 +/- 0.030 mu g/ml, respectively). A lower concentration producin g 50% of the maximal effect value was obtained for inhibition of serum TXB(2) concentration (0.023 +/- 0.004 mu g/l). Differences also were observed in equilibration half-life for these actions, suggesting the existence of 3 distribution compartments correlating with 3 sites of a ction-a central compartment and shallow and deep peripheral compartmen ts. Pharmacokinetic/pharmacodynamic modeling proved to be a useful ana lytical method, providing a quantitative description of in vivo drug p harmacodynamics and indicating possible mechanisms of action.