PHARMACODYNAMICS OF TOLFENAMIC ACID IN DOGS - EVALUATION OF DOSE-RESPONSE RELATIONSHIPS

Tolfenamic acid was administered to beagle dogs at 2, 4 and 8 mg/kg bodyweight i.m. and the concentration of drug in plasma and in inflamed (administered carrageenan) and non-inflamed subcutaneous tissue cage fluid was measured. The concentration of thromboxane B-2 in serum from blood allowed to clot under standardized conditions was determined and the concentrations of prostaglandin E(2), 12-hydroxyeicosatetraenoic acid (12-HETE) and leucocyte numbers were measured in fluid from the carrageenan administered tissue cages. Skin temperature was also measured over each tissue cage following administration of drug. Tolfenamic acid displayed linear pharmacokinetics since the area under the plasma concentration time curve (AUC) values were 13.74 +/- 1.88, 29.82 +/- 6.53 and 50.52 +/- 5.73 mu g/ml.h following administration of 2, 4 and 8 mg/kg, respectively. Tolfenamic acid proved to be a potent inhibitor of ex vivo thromboxane B-2 generation in clotting blood. Maximal inhibition was greater than 80% at all dose rates and 97% at the 8 mg/kg dose rate 1 h after drug administration. It also proved to be a potent inhibitor of prostaglandin E(2) production in inflammatory exudate, and significantly (P < 0.05) decreased prostaglandin E(2) production at all dose levels. Tolfenamic acid did not significantly alter 12-HETE generation or white blood cell accumulation in inflammatory exudate. Tolfenamic acid significantly reduced the elevated skin temperature over carrageenan administered cages at all dose levels.