Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation
1996; Wiley; Volume: 39; Issue: 12 Linguagem: Inglês
10.1002/art.1780391208
ISSN1529-0131
AutoresTaher Mahmud, Sue S. Rafi, David L. Scott, John M. Wrigglesworth, Ingvar Bjarnason,
Tópico(s)Pharmacogenetics and Drug Metabolism
ResumoAbstract 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 μ M ); 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.
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