Objective. There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal (GI) damage; it has been suggested that mucosal damage may be initiated by a "topical" action of NSAIDs involving mitochondrial injury. We evaluated the effect of a range of NSAIDs and related compounds on mitochondria] function and assessed the differences between them in relation to their physicochemical properties.Methods. Stimulation of respiration, as an indicator of mitochondrial uncoupling, was measured in isolated coupled rat liver mitochondrial preparations, using an oxygen electrode.Results. Conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations (0.02-2.7 +If); higher concentrations were inhibitory. The uncoupling potency was inversely correlated with drug pKa (r = -0.87, P < 0.001; n = 12). Drugs known to have good GI tolerability, including modified flurbiprofen (dimeroflurbiprofen and nitrobutyl-flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic highly selective COX-2 inhibitors, did not cause uncoupling.Conclusion. The ability to uncouple mitochondrial oxidative phosphorylation is a common characteristic of antiinflammatory agents with an ionizable group. Modification or absence of an ionizable moiety reduces the effect on mitochondria and could lead to improved NSAID GI safety.Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used, with more than 26 million and 100 million annual prescriptions in the UK and USA, respectively. The main concern about NSAID treatment is the risk of gastrointestinal (GI) damage. Non-ulcer endoscopic gastroduodenal lesions are seen in some 30-40% of patients receiving regular NSAID treatment, and peptic ulceration in 10-30% (1,2). In addition, long-term NSAID treatment causes small intestinal inflammation (NSAID enteropathy) (associated with blood and protein loss) in -65% of patients (3).The mechanism of this NSAID toxicity is unknown, but, similar to the mechanism of the drugs' antiinflammatory therapeutic effects (4), is widely believed to be related to inhibition of cyclooxygenase (COX) activity. However, there is substantial evidence that COX inhibition is not the only pertinent event, since 95% inhibition of COX activity has been achieved without apparent morphologic mucosal change ( 5 ) and mice with a disabled prostaglandin synthase 1 gene (resulting in the virtual absence of endogenous prostaglandin) do not spontaneously develop GI lesions. Paradoxically, these mice have been shown to be equally or less sensitive to the damaging effects of indomethacin, compared with controls (6). An alternative hypothesis is that NSAID-induced GI damage is initiated by a "topical" effect in which mitochondrial energy metabolism is disrupted (7), but alteration in prostanoid production is probably an important cofactor in the development of ulcers. NSAID ingestion results in increased activity of specific mitochondrial enzymes in rats a...

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Background-Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent "topical" action and by inhibiting cyclooxygenase. Aims-To discriminate between these two eVects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)-and (S)-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol. (Gut 1998;43:775-782) Methods-The

Background-Nitric oxide derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be much less ulcerogenic than their parent compounds. Aim-To compare the effect and potency of flurbiprofen and nitroxybutyl-flurbiprofen to uncouple mitochondrial oxidative phosphorylation (an early pathogenic event in NSAID enteropathy), increase intestinal permeability (transitional stage), and cause macroscopic small intestinal damage.