Measurement of cyclooxygenase inhibition in vivo: a study of two non-steroidal anti-inflammatory drugs in sheep

The anti-inflammatory effects of the non-steroidal anti-inflammatory drugs phenylbutazone (PBZ) and flunixin meglumine (FM) and the relationship between the effects and drug concentration in vivo were studied using a subcutaneous tissue-cage model in sheep. Intracaveal injection of carrageenan induced prostaglandin (PG) E-2 production in tissue-cage exudate (maximal concentration, 101 nM) with significant increases in white blood cell (WBC) numbers, skin temperature over the inflamed cage and exudate leukotriene B-4 (LTB4) concentration (P < 0.05). Intravenous PBZ, 4.4 mg kg(-1) produced mild inhibition of exudate PGE(2) generation (10%), but greater inhibition of serum TXB2 (75.3%). The IC50 for TXB2 was 36.0 mu M. Phenylbutazone did not alter effects on skin temperature, WBC numbers or exudate LTB4 concentrations. Intravenous FM, 1.1 mg kg(-1), significantly inhibited carrageenan-induced exudate PGE(2) formation (E-max, 100%, IC50, <0.4 nM) and serum TXB2 generation (E-max, 100%, IC50, 17 nM) for up to 32 h. Flunixin meglumine significantly inhibited the rise in skin temperature but had a limited effect on exudate WBC. Phenylbutazone and FM have distinct effects on carrageenan-induced cyclooxygenase (COX-2) and platelet COX (COX-1). Flunixin meglumine was a more potent COX inhibitor than PBZ and was more selective for the inducible form of COX in vivo.