title: Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation.
abstract: OBJECTIVE
  There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal anti-inflammatory 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 microM); 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 (dimero-flurbiprofen and nitrobutyl-flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic highly selective COX-2 inhibitors, did not cause uncoupling.
  
  
  CONCLUSIONS
  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.
authors.affiliation: King's College Hospital, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Mahmud
authors.forename: S S
authors.initials: SS
authors.lastname: Rafi
authors.forename: D L
authors.initials: DL
authors.lastname: Scott
authors.forename: J M
authors.initials: JM
authors.lastname: Wrigglesworth
authors.forename: I
authors.initials: I
authors.lastname: Bjarnason
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000633:toxicity*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005480:Flurbiprofen / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D005480:Flurbiprofen; C064874:DuP 697