Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety

• Published in: British journal of pharmacology Vol. 155; no. 6; pp. 857 - 864
• Main Authors: Chávez‐Piña, A E, Vong, L, McKnight, W, Dicay, M, Zanardo, R C O, Ortiz, M I, Castañeda‐Hernández, G, Wallace, J L
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2008; Nature Publishing Group
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Adhesion - physiology; COX; Dose-Response Relationship, Drug; Gastric Mucosa - metabolism; gastrointestinal; Indomethacin - analogs & derivatives; Indomethacin - pharmacology; leukocyte adherence; Leukocytes - metabolism; Male; Medical sciences; nitric oxide; NSAID; Pharmacology. Drug treatments; Rats; Rats, Wistar; Research Papers; Signal Transduction - physiology; Prostaglandin-endoperoxide synthase; Stomach; Acemetacin; Digestive system; Enzyme; Leukocyte; NSAID; leukocyte adherence; Gut; Enzyme inhibitor; Gastrointestinal; Adhesion; COX; Non steroidal antiinflammatory agent; Signal transduction; Nitric oxide; Indoleacetic acid derivatives; Oxidoreductases; Safety; Mechanism of action
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.316

Background and purpose: Acemetacin is a non‐steroidal anti‐inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin. Experimental approach: The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B4 and thromboxane B2, on leukocyte‐endothelial adherence in post‐capillary mesenteric venules, and on gastric expression of tumour necrosis factor‐α (TNF‐α) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX‐2 and NOS. Key results: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF‐α. Pretreatment with L‐nitro‐arginine methyl ester or lumiracoxib increased the severity of indomethacin‐induced gastric damage, but this was not the case with acemetacin. Conclusions and implications: The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte–endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene‐B4 synthesis and TNF‐α expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption. British Journal of Pharmacology (2008) 155, 857–864; doi:10.1038/bjp.2008.316; published online 11 August 2008