title: Effect of nimesulide action time dependence on selectivity towards prostaglandin G/H synthase/cyclooxygenase activity.
abstract: 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 PGG2 and the peroxidative reduction of PGG2 to form PGH2. 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 IC50 varied according to the time of pre-incubation (from 70 +/- 35 mumol/l to 0.07 +/- 0.05 mumol/l). Nimesulide did not affect COX-1 activity until 1 mumol/l and with an IC50 > 100 mumol/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-cyclohexyl-oxy-4-nitrophenyl)methane sulphonamide) and with flosulide and explains the different values of IC50 reported by other workers. Nimesulide shares with other sulfanilide-like drugs the time dependence of its selective effect on COX-2.
authors.affiliation: Servizio di Endocrinologia, Ospedale L. Sacco, Milan, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Vago
authors.forename: M
authors.initials: M
authors.lastname: Bevilacqua
authors.forename: G
authors.initials: G
authors.lastname: Norbiato
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D011451:Prostaglandin-Endoperoxide Synthases; C012655:nimesulide