title: Low direct cytotoxicity of nabumetone on gastric mucosal cells.
abstract: 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.
authors.affiliation: Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Arai
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Hironori
authors.initials: H
authors.lastname: Ushijima
authors.forename: Wataru
authors.initials: W
authors.lastname: Tomisato
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Mayuko
authors.initials: M
authors.lastname: Aburaya
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hoshino
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yokomizo
authors.forename: Keitarou
authors.initials: K
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Katsu
authors.forename: Tomofusa
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D002074:Butanones / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D000068579:Celecoxib; D018929:Cell Culture Techniques; D002463:Cell Membrane Permeability; D004912:Erythrocytes; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D006168:Guinea Pigs; D006461:Hemolysis; D000077430:Nabumetone; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D000077430:Nabumetone