Intestinal toxicity of ketoprofen-trometamol vs its enantiomers in rat. Role of oxidative stress

Objective: Gastrointestinal damage and bleeding are the major side effects of non-steroidal anti-inflammatory drugs (NSAID), however the mechanisms of this ulcerogenic action are not fully understood. It has recently been pro posed that neutrophil-and oxygen radical-dependent microvascular injuries m ay be important prime events that lead to mucosal injury. In addition, othe r factors like bile flow, intact bacterial flora or feeding conditions may contribute to the formation of lesions. Ketoprofen is a NSAID that exists a s a pair of R(-) and S(+) enantiomers; like other 2-arylpropionic acids, it s anti-inflammatory effects resides almost exclusively in the S (+) isomer. The present study was undertaken to explore the role of oxidative stress i n the pathogenesis of intestinal injury induced by oral administration of r acemic ketoprofen and its enantiomers given as their water soluble trometha mine salts. Material and methods. Evaluation of intestinal damage and activities of oxi dative stress related enzymes such as myeloperoxidase (MPO), xanthine-oxida se (XO) and superoxide dismutase (SOD) were studied in an experimental anim al model using refed rats. Results: After the oral treatment followed by a refeeding period of 24 h, k etoprofen (100, 50, 25 mg/Kg b.w.) dose-dependently caused longitudinal ulc ers on the mesenteric side of the middle and lower intestine lumen. The int estinal toxicity caused by S(+)-ketoprofen was significantly lower than the effect observed after racemate and R(-) enantiomer treatments (P < 0.001), though the bioinversion of R(-)-ketoprofen to S(+)-enantiomer that occurs in the rat has to be considered. XO activity was unaffected by the studied drugs. Enhanced enteropathy by the racemate and its R (-)-enantiomer was co rrelated with a significant increase of MPO activity as an index of neutrop hil infiltration, and a decrease in SOD activity (p<0.05 Vs control). S(+)- ketoprofen did not significantly change these parameters. Conclusions: These results suggest that reactive oxygen metabolites can con tribute significantly to the development of intestinal lesions, and that R( -)-ketoprofen present in racemic preparations can enhance the toxic intesti nal effects of S (+)-enantiomer via modification of neutrophil migration an d oxidative stress.