Intestinal Ulcerogenic Effect of S(+)‐Ketoprofen in the Rat

Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit prostaglandin synthesis 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 intestine are less common than those of the stomach, but intestinal lesions are more life threatening. Although the R(-)-enantiomers of the arylpropionic acid (APA) class of NSAIDs are assumed to lack the toxic effects of cyclooxygenase 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 weight of the tissue. Toxicity in the cecum was evaluated by measuring the size 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 does not show any effect in the cecum and only limited ulcerogenesis in the small intestine: The latter effect may be the result of racemic inversion. Therefore, the ulcerogenic action of racemic ketoprofen can be interpreted as a synergism between S(+)- and R(-)-ketoprofen. The mechanism of this synergism is not well understood but may be a general feature of APA NSAIDs.

Intestinal toxicity of ketoprofen-trometamol vs its enantiomers in rat. Role of oxidative stress

“…Under our experimental conditions, oral administration of S(+)-ketoprofen induced an ulcerogenic effect in the small intestine lower than those provoked by the double dose of the racemic form. These findings are in agreement with previously reported data in the rat [26] where acute oral administration of S(+)-ketoprofen causes significantly less ulcerogenicity in the small intestine than racemic ketoprofen does. In addition, our results tend to agree with those observed with rac-flurbiprofen and its enantiomers [13,14].…”

Wireless Capsule Endoscopy in Enteropathy Induced by Nonsteroidal Anti-inflammatory Drugs in Pigs

“…Most data on experimental NSAID-induced enteropathy have been published for acute or chronic studies using rat models [12][13][14][15][16][17][18][19][20][21]. We decided to use experimental pigs in our project because of similarities with human gastrointestinal anatomy and physiology [22].…”

Estimation of acute flurbiprofen and ketoprofen toxicity in rat gastric mucosa at therapy-relevant doses

“…Together with the finding that the S-enantiomers of flurbiprofen, ibuprofen and ketoprofen are more potent in inhibiting COX than the R-enantiomers [11,18] it would appear that the gastrotoxicity of FBP is primarily due to COX inhibition by S-FBP. In the rat intestine, though, it seems as if the R-enantiomer contributes significantly to the toxicity of racemic flurbiprofen free acid [19] and racemic ketoprofen-trometamol [11,25], which is explained by a COX-unrelated contribution of the R-enantiomers to drug toxicity. It follows that there are regional differences in the mucosal toxicity of arylpropionic acid NSAID enantiomers.…”