Development of in vitro assays for the evaluation of cyclooxygenase inhibitors and predicting selectivity of nonsteroidal anti-inflammatory drugs in cats
- 1 April 2005
- journal article
- research article
- Published by American Veterinary Medical Association (AVMA) in American Journal of Veterinary Research
- Vol. 66 (4), 700-709
- https://doi.org/10.2460/ajvr.2005.66.700
Abstract
Objective—To develop and validate in cats suitable in vitro assays for screening and ranking nonsteroidal antiinflammatory drugs (NSAIDs) on the basis of their inhibitory potencies for cyclooxygenase (COX)-1 and COX-2. Animals—10 cats. Procedure—COX-1 and COX-2 activities in heparinized whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. For the COX-2 assay, blood was pretreated with aspirin. The COX-1 and COX-2 assays were standardized, such that time courses of incubation with the test compounds and conditions of COX expression were as similar as possible in the 2 assays. Inhibition of thromboxane B2 production, measured by use of a radioimmunoassay, was taken as a marker of COX-1 and COX-2 activities. These assays were used to test 10 to 12 concentrations of a COX-1 selective drug (SC-560) and of 2 NSAIDs currently used in feline practice, meloxicam and carprofen. Selectivities of these drugs were compared by use of classic 50% and 80% inhibitory concentration (ie, IC50 and IC80) ratios but also with alternative indices that are more clinically relevant. Results—These assay conditions provide a convenient and robust method for the determination of NSAID selectivity. The S(+) enantiomeric form of carprofen was found to be COX-2 selective in cats, but meloxicam was only slightly preferential for this isoenzyme. Conclusions and Clinical Relevance—In vitro pharmacodynamic and in vivo pharmacokinetic data predict that the COX-2 selectivity of both drugs for cats will be limited when used at the recommended doses. This study provides new approaches to the selection of COX inhibitors for subsequent clinical testing. (Am J Vet Res 2005;66:700–709)Keywords
This publication has 32 references indexed in Scilit:
- Limitation of the in vitro whole blood assay for predicting the COX selectivity of NSAIDs in clinical useBritish Journal of Clinical Pharmacology, 2002
- Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine bloodAmerican Journal of Veterinary Research, 2002
- Eicosanoid production by human monocytes: does COX-2 contribute to a self-limiting inflammatory response?Inflammation Research, 2001
- Assay of cyclooxygenase-1 and 2 in human monocytesInflammation Research, 2000
- Functional Coupling of Cyclooxygenase 1 and 2 to Discrete Prostanoid Synthases in Liver MacrophagesBiochemical and Biophysical Research Communications, 2000
- Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the catResearch in Veterinary Science, 1996
- Evaluation of carprofen in calves using atissue cage model of inflammationBritish Veterinary Journal, 1996
- Stereospecific pharmacodynamics and pharmacokinetics of carprofen in the dogJournal of Veterinary Pharmacology and Therapeutics, 1994
- Pharmacodynamics and pharmacokinetics of carprofen in the horseEquine Veterinary Journal, 1994
- Pure Enantiomers of 2‐Arylpropionic Acids: Tools in Pain Research and Improved Drugs in RheumatologyThe Journal of Clinical Pharmacology, 1992