Stereoselective and substrate-dependent inhibition of hepatic mitochondrial beta-oxidation and oxidative phosphorylation by the non-steroidal anti-inflammatory drugs ibuprofen, flurbiprofen, and ketorolac

Non-steroidal anti-inflammatory drugs (NSAIDs) cause a range of adverse eff ects, some of which have been associated with perturbances of lipid metabol ic pathways. Previous data demonstrating stereoselective formation of the C oA thioester of R-ibuprofen in particular were suggestive of possible stere oselective effects on lipid metabolism Our aim was to characterise the rela tive stereoselectivity of the effects of ibuprofen, flurbiprofen, and ketor olac (0.01-1.0 mM) on both the beta-oxidation of palmitate and oxidative ph osphorylation in rat hepatic mitochondria as a means of dissecting prostagl andin related from non-prostaglandin-related events. beta-oxidation was inh ibited stereoselectively by R-ibuprofen (P = 0.015), non-stereoselectively by Rand S-flurbiprofen (P = 0.002 and P = 0.004, respectively), and was ess entially unaffected by either enantiomer of ketorolac. At 0.25 mM, inhibiti on by R-ibuprofen and both flurbiprofen enantiomers was partially reversed by increasing CoA concentrations (0-200 mu M). Mitochondrial respiration wa s moderately inhibited by both enantiomers of ibuprofen and flurbiprofen (P < 0.01), but only by high concentrations (greater than or equal to 1 mM) o f the enantiomers of ketorolac (P < 0.01). Uncoupling of oxidative phosphor ylation measured as stimulation of State 4 respiration contributed to these effects. The data support interactions involving both stereoselective CoA- dependent and non-CoA-dependent mechanisms. The plasma- drug concentrations required to achieve these effects are not likely to be attained in the maj ority of patients, although these concentrations are achievable in the gast rointestinal tract and may contribute to the well-known spectrum of adverse effects in this organ. Some patients do experience systemic adverse events which may be mediated by these mechanisms. (C) 1999 Elsevier Science Inc.