MECHANISM OF ENHANCEMENT OF INTESTINAL ULCEROGENICITY OF S-ARYL PROPIONIC ACIDS BY THEIR R-ENANTIOMERS IN THE RAT

We previously observed a marked increase in gastrointestinal toxicity of rac-flurbiprofen compared to the therapeutically equivalent dose of the S enantiomer. This paper quantitates these observations and exami nes the mechanism by which this paradoxical toxicity occurs. We have e valuated the ulcer scores, mucosal neutrophil infiltration, by immunos taining of CD11/18 antigen, and mucosal neutrophil activity by myelope roxidase measurement at two dose levels of (R)-, (S)-, and rac-flurbip rofen, administered over 30 days. Dose-response for intestinal ulcer p roduction was observed for rac- and (S)-flurbiprofen; animals given (R )flurbiprofen exhibited no ulcers, Yet rac-flurbiprofen proved to be t wice as ulcerogenic as (S)-flurbiprofen. The mechanism of the exacerba tion of gastrointestinal toxicity of (S)-flurbiprofen by the noncycloo xygenase inhibiting (R)-flurbiprofen is believed to be associated with its effect on ICAM-1 up-regulation. This is followed by neutrophil ad hesiveness to ICAM-1 via the LFA-1 antigen on its surface and the extr avasation of neutrophils into the tissue, We also examined the effect of high dose (R)-flurbiprofen vs vehicle over 15 days in animals in wh ich ulcers had been produced by treatment with (S)-flurbiprofen for th e previous 15 days. (R)-flurbiprofen did not sustain induced ulcers. T he results of this study suggest that human studies be conducted to de termine if enhanced gastrointestinal toxicity occurs in man. This is a t issue since rac compounds of this class are available over the count er and others may be introduced.