Abstract
BackgroundIn addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen.Methodology/Principal FindingsCOX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4′-hydroxyflurbiprofen and possibly also 3′-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds.Conclusions/SignificanceIt is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) mediate their anti-inflammatory, analgesic and antipyretic action by inhibiting production of prostaglandin intermediates by inhibition of cyclooxygenase isoenzymes 1 and/or 2 (COX-1, COX-2) [1]
NSAIDs are widely used their ability to produce serious unwanted cardiovascular and gastrointestinal effects means that there is a need for novel compounds with an improved safety profile
Binding of the NSAID to the allosteric site of the homodimer prevents endocannabinoid oxygenation, whereas inhibition of arachidonic acid (AA) oxygenation requires NSAID binding to the catalytic site [6,7]
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) mediate their anti-inflammatory, analgesic and antipyretic action by inhibiting production of prostaglandin intermediates by inhibition of cyclooxygenase isoenzymes 1 and/or 2 (COX-1, COX-2) [1]. An indomethacin analogue with pronounced selectivity for inhibition of COX-2 catalysed endocannabinoid oxygenation vs AA oxygenation has been described This compound increases endocannabinoid levels in the brain in vivo and produces potentially beneficial effects in models of anxiety [9], demonstrating that the ability of COX2 to metabolise endocannabinoids is a physiologically relevant pathway, at least in the brain. In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. We investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen
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