Effects of flurbiprofen and flurbinitroxybutylester on prostaglandin endoperoxide synthases.
The aim of our study was to evaluate the selectivity of flurbiprofen and flurbinitroxybutylester for inhibition of the cyclooxygenase activity of prostaglandin endoperoxide synthase-2 vs. prostaglandin endoperoxide synthase-1 in human blood monocytes and platelets, respectively. In whole blood, flurbiprofen was approximately 10-fold more potent that flurbinitroxybutylester to inhibit the cyclooxygenase activity of platelet prostaglandin endoperoxide synthase-1 (IC50 microM: 0.90 +/- 0.27 vs. 10.70 +/- 5, mean +/- S.D., P < 0.05). In contrast, the 2 compounds were equipotent to inhibit prostaglandin endoperoxide synthase-2 cyclooxygenase activity in whole blood (IC50 microM: 0.90 +/- 0.25 vs. 0.80 +/- 0.35) or isolated monocytes (IC50 microM: 0.03 +/- 0.02). Neither flurbiprofen nor flubinitroxybutylester (0.28-112 microM) affected prostaglandin endoperoxide synthase isozyme expression by lypopolysaccharide-stimulated monocytes. In whole blood, flurbinitroxybutylester was slowly converted to flubiprofen and this in turn could influence the extent of inhibition of the cyclooxygenase activity of prostaglandin endoperoxide synthase-1. In conclusion, the addition of a nitroxybutyl moiety to flurbiprofen seems to reduce its capacity to inhibit the cyclooxygenase activity of prostaglandin endoperoxide synthase-1. Whether this effect will result in a reduced risk of gastrointestinal toxicity remains to be studied in man.
Santini
G
G
Department of Pharmacology I, University of Chieti G. D'Annunzio School of Medicine, Palazzina delle Scuole di Specializzazione, Italy.
Sciulli
M G
MG
Panara
M R
MR
Padovano
R
R
di Giamberardino
M
M
Rotondo
M T
MT
Del Soldato
P
P
Patrignani
P
P
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000494:pharmacology*; D001792:Blood Platelets / Q000201:enzymology; D016861:Cyclooxygenase Inhibitors / Q000097:blood* / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000097:blood; D004355:Drug Stability; D005260:Female; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000097:blood*; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; C095631:nitroflurbiprofen; D013929:Thromboxane B2; D005480:Flurbiprofen; D015232:Dinoprostone