INTESTINAL TOLERABILITY OF NITROXYBUTYL-FLURBIPROFEN IN RATS

Background-Nitric oxide derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be much less ulcerogenic than their par ent compounds, Aim-To compare the effect and potency of flurbiprofen a nd nitroxybutyl-flurbiprofen to uncouple mitochondrial oxidative phosp horylation (an early pathogenic event in NSAID enteropathy), increase intestinal permeability (transitional stage), and cause macroscopic sm all intestinal damage. Methods-In vitro uncoupling potency was assesse d using isolated coupled rat Liver mitochondria and in vivo by electro n microscopy of rat small intestinal mucosa (two hours after the drugs ). A dose-response study with flurbiprofen (single doses of 5, 10, 20, and 40 mg/kg) and equimolar doses of nitroxybutyl-flurbiprofen was pe rformed; assessing their effect on intestinal permeability (at 18-20 h ours), with Cr-51 EDTA, and the number of pointed (<5 mm) and longitud inal (>5 mm) small intestinal ulcers at 24 hours. Results-Flurbiprofen , but not nitroxybutyl-flurbiprofen, stimulated coupled respiration in vitro. Both drugs, however, uncoupled in vivo; in the case of nitroxy butyl-flurbiprofen possibly because hydrolysis of its ester bond relea sed free flurbiprofen. Intestinal permeability was uniformly and equal ly increased with both drugs compared with controls. The number of sma ll intestinal ulcers, pointed and longitudinal, was significantly redu ced with nitroxybutyl-flurbiprofen apart from the number of longitudin al ulcers with the highest dose. Conclusions-These studies show that n itroxybutyl-flurbiprofen is associated with significantly less macrosc opic damage in the small intestine than flurbiprofen but was associate d with mitochondrial damage in vivo and caused similar increases in pe rmeability of the small intestine, Suggesting that its beneficial effe ct is on the later pathogenic stages of the damage.