EXPERIMENTAL-MODELS USED TO INVESTIGATE THE DIFFERENTIAL INHIBITION OF CYCLOOXYGENASE-1 AND CYCLOOXYGENASE-2 BY NONSTEROIDAL ANTIINFLAMMATORY DRUGS

Numerous in vitro assays have been developed for testing and comparing the relative inhibitory activities of non-steroidal anti-inflammatory drugs against cyclooxygenase (COX)-1 and COX-2. Despite variability a mong these systems, which precludes direct comparison of data, analysi s of the ratio of inhibition of COX-1 to COX-2 by non-steroidal anti-i nflammatory drugs, suggests inhibitors can be classified based on thei r COX selectivity. Standard non-steroidal antiinflammatory drugs can b e considered nonselective; compounds such as meloxicam and nimesulide can be classified as COX-2 preferential; and compounds such as SC 5812 5 and L-754,337 are selective for COX-2. Although in vitro systems are important for characterizing COX-1 and COX-2 inhibitory activity, the clinical relevance of these data should be considered carefully. The level of inhibition of COX-I and COX-2, in vivo at a given dose in pat ients, cannot be predicted from in vitro data alone. The pharmacokinet ic properties of each compound including plasma levels, distribution a nd binding to plasma proteins, have to be taken into account. Human ph armacology studies concentrating on the inhibition of prostanoid synth esis in target tissues are of paramount importance in determining the clinical relevance of COX-2 selectivity.