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 examines the mechanism by which this paradoxical toxicity occurs. We have evaluated the ulcer scores, mucosal neutrophil infiltration, by immunostaining of CD11/18 antigen, and mucosal neutrophil activity by myeloperoxidase measurement at two dose levels of (R)-, (S)-, and rac-flurbiprofen, administered over 30 days. Dose-response for intestinal ulcer production was observed for rac- and (S)-flurbiprofen; animals given (R)-flurbiprofen exhibited no ulcers. Yet rac-flurbiprofen proved to be twice as ulcerogenic as (S)-flurbiprofen. The mechanism of the exacerbation of gastrointestinal toxicity of (S)-flurbiprofen by the noncyclooxygenase inhibiting (R)-flurbiprofen is believed to be associated with its effect on ICAM-1 up-regulation. This is followed by neutrophil adhesiveness to ICAM-1 via the LFA-1 antigen on its surface and the extravasation of neutrophils into the tissue. We also examined the effect of high dose (R)-flurbiprofen vs vehicle over 15 days in animals in which ulcers had been produced by treatment with (S)-flurbiprofen for the previous 15 days. (R)-flurbiprofen did not sustain induced ulcers. The results of this study suggest that human studies be conducted to determine if enhanced gastrointestinal toxicity occurs in man. This is at issue since rac compounds of this class are available over the counter and others may be introduced.