Addition of a nitroxybutyl moiety to
diclofenac greatly reduces its damaging effects on the gastric mucosa without altering its ability to suppress
prostaglandin synthesis and exert anti-inflammatory actions. The present study was performed in order to determine if this derivative of
diclofenac, called
nitrofenac, would also have less toxicity in the small and large intestine when administered repeatedly over a 1-2 week period. Healthy rats were given equimolar doses of
diclofenac (10 mg/kg) or
nitrofenac (15 mg/kg) twice daily for up to two weeks. All 10 rats receiving
diclofenac died prior to completion of the study, exhibiting massive small intestinal ulceration and perforation. No deaths were observed in the rats treated with
nitrofenac, and the only small intestinal abnormality observed was diffuse
hyperemia. As nonsteroidal anti-inflammatory drugs have been shown to exacerbate
colitis, we compared the effects of twice daily treatment with
diclofenac (1-10 mg/kg) or
nitrofenac (1.5-15 mg/kg) for 1 week in rats in which
colitis had been induced with trinitrobenzene
sulfonic acid.
Diclofenac administration resulted in mortality which increased dose-dependently (e.g. 86% at 5 mg/kg) and was associated with perforation of the colon. Mortality was not observed with
nitrofenac at doses of 1.5 or 7.5 mg/kg, while at 15 mg/kg the mortality rate was 33%. None of the doses of
nitrofenac significantly augmented colonic injury or granulocyte infiltration (measured by
myeloperoxidase activity). Suppression of colonic
prostaglandin E2 synthesis was comparable with equimolar doses of
diclofenac and nitrofenace. These studies demonstrate that
nitrofenac has markedly reduced intestinal toxicity in healthy and colitic rats when compared to
diclofenac.