Effect of nimesulide action time dependence on selectivity towards prostaglandin G/H synthase/cyclooxygenase activity
Vago, T.; Bevilacqua, M.; Norbiato, G.
Arzneimittel-Forschung 45(10): 1096-1098
1995
ISSN/ISBN: 0004-4172 PMID: 8595067 Document Number: 446883
PGHS (cyclooxygenase, prostaglandin endoperoxide synthase, 8.11.14-icosatrienoate hydrogen donor oxygen oxidoreductase, EC 1.14.99.1) is a bifunctional, membrane-bound hemoprotein that catalyzes both the bisoxygenation of arachidonic acid to form PGG-2 and the peroxidative reduction of PGG-2 to form PGH-2. Recently two forms of cyclooxygenase have been isolated, one (COX-1) being "constitutive", the other (COX-2) being mitogen-inducible. Nimesulide (CAS 51803-78-2) has been shown to inhibit with high selectivity COX-2 without affecting COX-1 activity, so explaining the previous observations about the selectivity of the anti-prostaglandin effect of the drug. The potency of the effect, however, seems to be different according to these works. The time dependence of COX-2 inhibitors might afford some clues to a better understanding of the mechanism of COX-2 selective inhibition, on the discrepancy between some authors about the potency of the drug and on the relationship between COX-2 inhibition and inhibition of superoxide anion production, an event also characterized by a time dependence. So we evaluated the time dependency of the effect of nimesulide on COX-1 and COX-2. COX-1 was isolated from ram seminal vesicles, and COX-2 was from sheep placenta. Nimesulide inhibited COX-2 activity in a concentration-dependent manner. The inhibition of COX-2 was characterized by the time dependence, so the IC-50 varied according to the time of pre-incubation (from 70 +- 35 mu-mol/l to 0.07 +- 0.05 mu-mol/l). Nimesulide did not affect COX-1 activity until 1 mu-mol/l and with an IC-50 gt 100 mu-mol/l. In conclusion nimesulide's selective inhibitory effect on COX-2 is time-dependent whereas its weak effect on COX-1 is not time-dependent. This observation agrees with the time dependence effect of COX-2 reported by other workers with NS-398 (N-(2-cyclohexyloxy-4-nitrophenyl) methane sulphonamide) and with flosulide and explains the different values of IC-50 reported by other workers. Nimesulide shares with other sulfanilide-like drugs the time dependence of its selective effect on COX-2.