Mechanisms involved in the attenuation of intestinal toxicity induced by (S)-(+)-ketoprofen in re-fed rats.

In addition to suppression of prostaglandins synthesis a number of factors have been implicated in nonsteroidal antiinflammatory drugs (NSAIDs) enteropathy, including oxygen radical-dependent microvascular injuries, depletion of glutathione, and food. Inflammatory cytokines such as tumor necrosis factor-alpha regulate endothelial adhesion molecules expression and promote vascular neutrophil adherence. Racemic ketoprofen is a potent NSAID with a chiral structure existing in two enantiomeric forms. Its therapeutic effects reside almost exclusively in the (S)-(+) isomer nevertheless the potential contribution to side effects of the (R)-(-) isomer cannot be ignored. The aims of this study were to explore the role of prostaglandins depletion, tumor necrosis factor-alpha production, and glutathione homeostasis in the comparative pathogenesis of intestinal injury induced by racemic-ketoprofen and its enantiomers in re-fed rats. Racemic ketoprofen and (R)-(-)-ketoprofen dose-dependently caused similar and multiple lesions in the mid-jejunum significantly higher than those observed with (S)-(+)-ketoprofen. All the treatments significantly decreased prostaglandins content. A significant increase of tumor necrosis factor-alpha production and decreases in glutathione levels and glutathione reductase activity after treatment of the racemate and (R)-(-)-ketoprofen, were observed whereas the (S)-(+)-isomer did not change these parameters. In conclusion, (S)-(+)-ketoprofen possesses a better intestinal toxicity profile than the racemate and its (R)-(-)-isomer. Despite inhibiting cyclooxygenase activity, the attenuation of (S)-(+)-ketoprofen-induced intestinal toxicity could be correlated with a reduced oxidative damage characterized not only by a lack of changes in glutathione reductase activity and glutathione levels but also by an absence of up-regulation of tumor necrosis factor-alpha production in intestinal mucosa.