Evaluation of selective inhibition of canine cyclooxygenase 1 and 2 by carprofen and other nonsteroidal anti-inflammatory drugs.
OBJECTIVE
To evaluate the activity of carprofen and other nonsteroidal anti-inflammatory drugs (NSAID) against isozymes of canine cyclooxygenases (COX1 and COX2).


METHODS
Constitutive COX1 was obtained from washed canine platelets, and COX2 was obtained from a canine macrophage-like cell line that was induced with endotoxin. Activity of carprofen and other NSAID against COX1 and COX2 was compared. Dose-response curves were plotted, and calculations were performed to identify concentrations that caused 50% inhibition (IC50 [microM]) for each isozyme. Ratio of the COX1-to-COX2 IC50 was used as a measure of isozyme selectivity.


RESULTS
Of the compounds evaluated, carprofen had the greatest selectivity for COX2. Potency of carprofen for canine COX2 was more than 100-fold greater than for canine COX1. Inhibition of canine COX2 (IC50, 0.102 microM) for the racemic mixture of carprofen (S and R stereoisomers) was primarily attributable to the S enantiomer (IC50, 0.0371 microM), which was approximately 200-fold more potent than the R enantiomer (IC50, 5.97 microM). Nimesulide had the next highest selectivity for COX2 (38-fold), and tolfenamic acid and meclofenamic acid had 15-fold selectivity for COX2. The other compounds tested did not have substantial selectivity for canine COX2 or were more selective for canine COX1.


CONCLUSIONS
Carprofen was found to be a potent inhibitor of canine COX2. Of the compounds tested, carprofen had the highest selectivity for canine COX2.


CONCLUSIONS
The selectivity of carprofen for canine COX2 may be an important factor for its use in dogs.
Ricketts
A P
AP
Central Research Division, Pfizer Inc, Groton, CT 06340, USA.
Lundy
K M
KM
Seibel
S B
SB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004285:Dogs / Q000097:blood*; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013929:Thromboxane B2 / Q000032:analysis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002227:Carbazoles; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007476:Ionophores; D007527:Isoenzymes; D000001:Calcimycin; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C007005:carprofen