EFFECTS OF NIMESULIDE ON CONSTITUTIVE AND INDUCIBLE PROSTANOID BIOSYNTHESIS IN HUMAN-BEINGS

Background: The aim of this study was to test the hypothesis that nime sulide, a nonsteroidal antiinflammatory drug, or its principal metabol ite 4-hydroxynimesulide, is a selective inhibitor of prostaglandin H s ynthase-2 in human beings. Methods: Heparinized whole blood samples ob tained from healthy subjects were incubated with lipopolysaccharide (1 0 mu g/ml) for 24 hours at 37 degrees C and prostaglandin E-2 was meas ured in plasma as an index of monocyte prostaglandin H synthase-2 acti vity. The production of thromboxane B-2 in whole blood allowed to clot at 37 degrees C for 60 minutes was assessed as an index of platelet p rostaglandin H synthase-1 activity, We also measured the urinary excre tion of 11-dehydrothromboxane B-2, prostaglandin E-2, 6-ketoprostaglan din F-1 alpha, and thromboxane B-2 as in vivo indexes of cyclooxygenas e activity. All prostanoids were measured by previously validated radi oimmunoassay techniques. Results: In the whole blood assays in vitro, nimesulide was twenty-fold more potent than 4-hydroxynimesulide toward the two isozymes and both compounds displayed a twentyfold preference for prostaglandin H synthase-2 versus prostaglandin H synthase-1. The administration of a single oral dose of 100 mg nimesulide to sin heal thy subjects significantly (p < 0.01) reduced monocyte prostaglandin H synthase-2 and prostaglandin H synthase-1 activity ex vivo by more th an 90% and 50%, respectively, up to 6 hours. At 24 hours, prostaglandi n H synthase-2 but not prostaglandin H synthase-1 activity was signifi cantly reduced by 49% (p < 0.05), Nimesulide significantly (p < 0.05) reduced the urinary excretion of 11-dehydrothromboxane B-2 and 6-ketop rostaglandin F-1 alpha by approximately 30% and 25%, respectively, whi le not affecting that of prostaglandin E-2 and thromboxane B-2. Conclu sions: Nimesulide is a potent inhibitor of human monocyte prostaglandi n H synthase-2, However, despite a twentyfold selectivity ratio, thera peutic plasma levels of nimesulide are sufficiently high to cause dete ctable inhibition of platelet prostaglandin H synthase-1.