Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation

Abstract

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 mitochondrial 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 μM); 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.