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) E2 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 B4 (LTB4) concentration (P < 0.05). Intravenous PBZ, 4.4 mg kg-1 produced mild inhibition of exudate PGE2 generation (10%), but greater inhibition of serum TXB2 (75.3%). The IC50 for TXB2 was 36.0 microM. 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 PGE2 formation (Emax, 100%, IC50, < 0.4 nM) and serum TXB2 generation (Emax, 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.
Cheng
Z
Z
Department of Veterinary Preclinical Studies, University of Glasgow, UK.
Nolan
A M
AM
McKellar
Q A
QA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D002351:Carrageenan / Q000008:administration & dosage; D003002:Clonixin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015194:Diffusion Chambers, Culture; D015232:Dinoprostone / Q000096:biosynthesis; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007527:Isoenzymes / Q000097:blood / Q000378:metabolism; D007958:Leukocyte Count; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D010653:Phenylbutazone / Q000493:pharmacokinetics / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood / Q000378:metabolism; D012756:Sheep; D012881:Skin Temperature / Q000187:drug effects; D013929:Thromboxane B2 / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007975:Leukotriene B4; D013929:Thromboxane B2; C014558:flunixin meglumine; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010653:Phenylbutazone; D015232:Dinoprostone; D003002:Clonixin