Elsevier

Biochemical Pharmacology

Volume 57, Issue 7, 1 April 1999, Pages 837-844
Biochemical Pharmacology

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

https://doi.org/10.1016/S0006-2952(98)00342-6Get rights and content

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) cause a range of adverse effects, some of which have been associated with perturbances of lipid metabolic pathways. Previous data demonstrating stereoselective formation of the CoA thioester of R-ibuprofen in particular were suggestive of possible stereoselective effects on lipid metabolism. Our aim was to characterise the relative stereoselectivity of the effects of ibuprofen, flurbiprofen, and ketorolac (0.01–1.0 mM) on both the β-oxidation of palmitate and oxidative phosphorylation in rat hepatic mitochondria as a means of dissecting prostaglandin related from non-prostaglandin-related events. β-oxidation was inhibited stereoselectively by R-ibuprofen (P = 0.015), non-stereoselectively by R- and S-flurbiprofen (P = 0.002 and P = 0.004, respectively), and was essentially unaffected by either enantiomer of ketorolac. At 0.25 mM, inhibition by R-ibuprofen and both flurbiprofen enantiomers was partially reversed by increasing CoA concentrations (0–200 μM). Mitochondrial respiration was moderately inhibited by both enantiomers of ibuprofen and flurbiprofen (P < 0.01), but only by high concentrations (≥1 mM) of the enantiomers of ketorolac (P < 0.01). Uncoupling of oxidative phosphorylation 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 majority of patients, although these concentrations are achievable in the gastrointestinal 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.

Section snippets

Chemicals and reagents

S(+)- and R(−)-ibuprofen (99% optically pure) and S(+)- and R(−)-flurbiprofen (95.7% optically pure) were supplied by The Boots Company P/L. S(−)-ketorolac (96.4% optically pure) and R(+)-ketorolac (>99% optically pure) were supplied by Syntex Laboratories Inc. Reagents and chemicals were obtained from the following sources: methoxyflurane (Penthrane), Abbott Australasia; ATP, CoA lithium salt, l-carnitine.HCl, BSA, Tris hydrochloride and base, and ADP potassium salt, Sigma Chemical Co.;

Effects of NSAID enantiomers on mitochondrial β-oxidation

There was a significant relationship between the concentrations of both R- and S-ibuprofen and inhibition of the β-oxidation of palmitate by rat hepatic mitochondria when assessed as inhibition of formation of acid-soluble products (Fig. 1a; P = 0.0001). R-ibuprofen was much more potent than its S-antipode when assessed by the general linear models procedure (P = 0.015). The effects of R- and S-flurbiprofen (Fig. 1b) on the oxidation of palmitate were similar (P = 0.002, P = 0.004,

Discussion

The stereoselective inhibition of β-oxidation displayed by R-ibuprofen was consistent with previous data 1, 2, supporting the conclusion that a CoA-dependent mechanism was involved, although the degree of inhibition was rather greater in the present study. However, S-ibuprofen also inhibited β-oxidation, albeit less potently, while both enantiomers of flurbiprofen were inhibitory. This suggested that a non-CoA-dependent process was also involved, because previous data have indicated that S

Acknowledgements

This study was supported by an NHMRC grant to K.W. and R.D., and by the Boots Company, PLC (U.K.). The authors also wish to thank Dr. Kathleen Knights (Flinders University, Adelaide), Dr. Mark Hicks (St Vincents, Sydney), and Dr. Eric Brass (Harbor-UCLA Medical School, CA) for advice, and Dr. Gerd Geisslinger (Erlangen, Germany) for the purity assessment of the ketorolac enantiomers.

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