Intestinal ulcerogenic effect of S(+)-ketoprofen in the rat

Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit prostaglandin synthesi s in the gastrointestinal mucosa, which can lead not only to stomach ulcers but also ulcers in the small and large intestines. Ulcers of the small int estine are less common than those of the stomach, but intestinal lesions ar e more life threatening. Although the R(-)-enantiomers of the arylpropionic acid (APA) class of NSAIDs are assumed to lack the toxic effects of cycloo xygenase inhibition, they may contribute to the ulcerogenicity of racemates . We have examined the intestinal ulcerogenic effects of single oral doses of S(+)-ketoprofen compared with racemic ketoprofen in the small intestine and cecum of rats. The toxicity in the small intestine was measured as the weight ratio between portions of intestine showing lesions and the total we ight of the tissue. Toxicity in the cecum was evaluated by measuring the si ze of the ulcers. S(+)-ketoprofen had no significant ulcerogenic effect at 10 or 20 mg/kg. However, racemic ketoprofen was clearly ulcerogenic in the small intestine and cecum at the 40 mg dose. R(-)-ketoprofen at 20 mg/kg do es not show any effect in the cecum and only limited ulcerogenesis in the s mall intestine: The latter effect may be the result of racemic inversion. T herefore, the ulcerogenic action of racemic ketoprofen can be interpreted a s a synergism between S(+)- and R(-)-ketoprofen. The mechanism of this syne rgism is not well understood but may be a general feature of APA NSAIDs. Jo urnal of Clinical Pharmacology, 1998;38:27S-32S (C) 1998 The American Colle ge of Clinical Pharmacology.