Ibuprofen inhibits the metabolism of the endogenous cannabimimetic agent anandamide

Abstract

A measure of the metabolism of anandamide, an endogenous cannabimimetic agent, by rat cerebellar membrane preparations was obtained by following the time-dependent reduction in potency of this compound towards inhibition of binding of the high-affinity cannabinoid agonist ligand [3H]WIN 55212-2 to cannabinoid receptors. Thus for example, incubation of the membranes with 100 nM anandamide for 0, 10 and 30 min. prior to addition of [3H]WIN 55212-2 and phenylmethylsulphonyl fluoride (to inhibit the activity of anandamide amidase, thereby blocking further anandamide metabolism during the binding assay) produced 57 ± 3, 38 ± 5 and 19 ± 7 % inhibition, respectively, of [3H]WIN 55212-2 binding. This time-dependent effect was blocked by ibuprofen but not by acetyl salicylic acid, sulindac, acetaminophen or to any significant extent by ketoprofen and naproxen. Preliminary experiments using a direct assay of anandamide amidase with [14C]anandamide as ligand gave an IC50 value for ibuprofen of ~ 400 μM. The potency of ibuprofen as an inhibitor of anandamide metabolism was of the same order of magnitude as required for inhibition of cyclooxygenase-2 in cell-free systems and of the peak plasma concentrations of this drug following a 2 x 200 mg dose regimen. It is concluded that following therapeutic doses of ibuprofen, the metabolism of anandamide may be affected.