NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND UNCOUPLING OF MITOCHONDRIAL OXIDATIVE-PHOSPHORYLATION

Objective. There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal antiinflammatory drug (NSAID)-induced gas trointestinal (GI) damage; it has been suggested that mucosal damage m ay be initiated by a ''topical'' action of NSAIDs involving mitochondr ial injury. We evaluated the effect of a range of NSAIDs and related c ompounds on mitochondrial function and assessed the differences betwee n them in relation to their physicochemical properties. Methods. Stimu lation of respiration, as an indicator of mitochondrial uncoupling, wa s measured in isolated coupled rat liver mitochondrial preparations, u sing an oxygen electrode. Results. Conventional NSAIDs and acidic prod rugs all had stimulatory effects on mitochondrial respiration at micro molar concentrations (0.02-2.7 mu M); higher concentrations were inhib itory, The uncoupling potency was inversely correlated with drug pKa ( r = -0.87, P < 0.001; n = 12), Drugs known to have good GI tolerabilit y, including modified flurbiprofen (dimero-flurbiprofen and nitrobutyl -flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic high ly selective COX-2 inhibitors, did not cause uncoupling. Conclusion. T he ability to uncouple mitochondrial oxidative phosphorylation is a co mmon 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.