Mechanism of Enhancement of Intestinal Ulcerogenicity of S-Aryl Propionic Acids by Their R-Enantiomers in the Rat

We previously observed a marked increase ingastrointestinal toxicity of rac -flurbiprofen comparedto the therapeutically equivalent dose of the Senantiomer. This paper quantitates these observations and examines the mechanism by which thisparadoxical toxicity occurs. We have evaluated the ulcerscores, mucosal neutrophil infiltration, byimmunostaining of CD11/18 antigen, and mucosalneutrophil activity by myeloperoxidase measurement at two doselevels of (R)-, (S)-, and rac-flurbiprofen, administeredover 30 days. Dose-response for intestinal ulcerproduction was observed for rac- and (S)-flurbiprofen; animals given (R)flurbiprofen exhibited noulcers. Yet rac-flurbiprofen proved to be twice asulcerogenic as (S)-flurbiprofen. The mechanism of theexacerbation of gastrointestinal toxicity of(S)flurbiprofen by the noncyclooxygenase inhibiting(R)-flurbiprofen is believed to be associated with itseffect on ICAM-1 up-regulation. This is followed byneutrophil adhesiveness to ICAM-1 via the LFA-1 antigenon its surface and the extravasation ofneutrophils into the tissue. We also examined the effectof high dose (R)-flurbiprofen vs vehicle over 15 days inanimals in which ulcers had been produced by treatment with (S)-flurbiprofen for the previous 15 days.(R)-flurbiprofen did not sustain induced ulcers. Theresults of this study suggest that human studies beconducted to determine if enhanced gastrointestinal toxicity occurs in man. This is at issue sincerac compounds of this class are available over thecounter and others may be introduced.