ENANTIOMERS OF FLURBIPROFEN CAN DISTINGUISH KEY PATHOPHYSIOLOGICAL STEPS OF NSAID ENTEROPATHY IN THE RAT

Background-Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastro intestinal damage by a non-prostaglandin (PG) dependent ''topical') ac tion and by inhibiting cyclooxygenase. Aims-To discriminate between th ese two effects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)- and (S)flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol. Methods-The effects of dinitrophenol, racemic, (R)-, and (S)-flurbiprofen on mitochondria were assessed in vitro and on key pathophysiological features of smal l intestinal damage in vivo (ultrastructure by electron microscopy, mu cosal prostanoid concentrations, Intestinal permeability, inflammation , and ulcer count) in rats. Results-All the drugs uncoupled mitochondr ial oxidative phosphorylation in vitro, caused mitochondrial damage in vivo, and increased intestinal permeability. Dinitrophenol and (R)-fl urbiprofen caused no significant decreases in mucosal prostanoid conce ntrations (apart from a decrease in thromboxane CTX) B, concentrations following (R)flurbiprofen) while racemic and (S)- flurbiprofen reduce d mucosal prostanoids significantly (PGE, TXB2, and 6-keto-PGF(1a) con centrations by 73-95%). Intestinal inflammation was significantly grea ter following administration of (S)flurbiprofen and racemate than with dinitrophenol and (R)-flurbiprofen. No small intestinal ulcers were f ound following dinitrophenol or (R)-flurbiprofen while both racemic an d (S)-flurbiprofen caused numerous ulcers. Conclusions-Dinitro phenol and (R) flurbiprofen show similarities in their actions to uncouple mi tochondrial oxidative phosphorylation in vitro, alter mitochondrial mo rphology in vivo, increase intestinal permeability, and cause mild inf lammation without ulcers. Concurrent severe decreases in mucosal prost anoids seem to be the driving force for the development of severe infl ammation and ulcers.