Low direct cytotoxicity of nabumetone on gastric mucosal cells

• Published in: Digestive diseases and sciences Vol. 50; no. 9; pp. 1641 - 1646
• Main Authors: ARAI, Yasuhiro, TANAKA, Ken-Ichiro, TSUCHIYA, Tomofusa, MIZUSHIMA, Tohru, USHIJIMA, Hironori, TOMISATO, Wataru, TSUTSUMI, Shinji, ABURAYA, Mayuko, HOSHINO, Tatsuya, YOKOMIZO, Kazumi, SUZUKI, Keitarou, KATSU, Takashi
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.09.2005; Springer Nature B.V
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Butanones - administration & dosage; Butanones - adverse effects; Butanones - pharmacology; Celecoxib; Cell Culture Techniques; Cell Membrane Permeability; Erythrocytes; Gastric Mucosa - cytology; Gastric Mucosa - drug effects; Gastric Mucosa - pathology; Guinea Pigs; Hemolysis; Medical sciences; Pharmacology. Drug treatments; Pyrazoles - adverse effects; Pyrazoles - pharmacology; Rats; Severity of Illness Index; Sulfonamides - adverse effects; Sulfonamides - pharmacology; Prostaglandin-endoperoxide synthase; Stomach; Enzyme; Mucosa; Enzyme inhibitor; Cytotoxicity; membrane permeabilization: gastric lesions; Non steroidal antiinflammatory agent; Nabumetone; Analgesic; gastric mucosal cells; Antipyretic; Oxidoreductases; Lesion
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-005-2909-x

Prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for clinical purposes because they are not harmful to the gastrointestinal mucosa. We recently showed that NSAIDs have direct cytotoxicity in NSAID-induced gastric lesions. We show here that under conditions where the NSAIDs indomethacin and celecoxib clearly induce cell death, an NSAID prodrug, nabumetone, and its active metabolite 6-methoxy-2-naphthylacetic acid (6MNA), did not have such effects. Moreover, nabumetone and 6MNA exhibited much lower membrane permeabilizing activities than did indomethacin and celecoxib. We recently reported that when an orally administered NSAID was used in combination with a low dose of intravenously administered indomethacin, the severity of gastric lesions produced in rats depended on the cytotoxicity of the orally administered NSAID. Using a similar protocol, we show here that gastric lesions were produced when the orally administered NSAID was celecoxib, but not when nabumetone was used. We thus propose that the low direct cytotoxicity of nabumetone observed in vitro is maintained in vivo, and that the use of nabumetone does not harm the gastric mucosa.