Background-The "topical" eVect of nonsteroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage. Aim-To examine the possible mechanism of the "topical" phase of damage in the small intestine. Methods-Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode. Results-The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the "topical" phase of NSAID induced damage. Conclusion-Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the "topical" phase of damage induction.

These studies allow dissociation of the contribution and consequences of uncoupling of mitochondrial oxidative phosphorylation and cyclooxygenase inhibition in the pathophysiology of NSAID enteropathy. While uncoupling of enterocyte mitochondrial oxidative phosphorylation leads to increased intestinal permeability and low grade inflammation, concurrent decreases in mucosal prostanoids appear to be important in the development of ulcers.

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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...