Effects of flurbiprofen and flurbinitroxybutylester on prostaglandin endoperoxide synthases

• Published in: European journal of pharmacology Vol. 316; no. 1; pp. 65 - 72
• Main Authors: Santini, Giovanna, Sciulli, Maria G., Panara, Maria R., Padovano, Roberto, di Giamberardino, Maria, Rotondo, Maria T., Del Soldato, Piero, Patrignani, Paola
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 28.11.1996; Elsevier
• Subjects: Adult; Anti-Inflammatory Agents, Non-Steroidal - blood; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Blood monocyte, human; Blood Platelets - enzymology; Cyclooxygenase Inhibitors - blood; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - biosynthesis; Dinoprostone - blood; Drug Stability; Drug toxicity and drugs side effects treatment; Female; Flurbinitroxybutylester; Flurbiprofen; Flurbiprofen - analogs & derivatives; Flurbiprofen - blood; Flurbiprofen - pharmacology; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - blood; Leukocytes, Mononuclear - enzymology; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Platelet, human; Prostaglandin endoperoxide synthase; Thromboxane B2 - biosynthesis; Thromboxane B2 - blood; Toxicity: digestive system; Flurbinitroxybutylester; Platelet, human; Prostaglandin endoperoxide synthase; Blood monocyte, human; Flurbiprofen; Human; Stomach; Prostaglandin-endoperoxide synthase; Monocyte; Enzyme; Digestive system; Toxicity; Biological model; Enzyme inhibitor; Selectivity; In vitro; Biological activity; Non steroidal antiinflammatory agent; Whole blood; Blood cell; Platelet; Arylacetic acid derivatives; Structure activity relation; Isolated cell; Secondary effect; Oxidoreductases; Comparative study
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(96)00640-1

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 than flurbinitroxybutylester to inhibit the cyclooxygenase activity of platelet prostaglandin endoperoxide synthase-1 (IC 50 μM: 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 (IC 50 μM: 0.90 ± 0.25 vs. 0.80 ± 0.35) or isolated monocytes (IC 50 μM: 0.03 ± 0.02 vs. 0.03 ± 0.02). Neither flurbiprofen nor flurbinitroxybutylester (0.28–112 μM) affected prostaglandin endoperoxide synthase isozyme expression by lypopolysaccharide-stimulated monocytes. In whole blood, flurbinitroxybutylester was slowly converted to flurbiprofen 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.