Ibuprofen inhibits the metabolism of the endogenous cannabimimetic agent anandamide

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 [H-3]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 [C-14]anandamide as ligand gave an IC50 value for ibuprofen of similar to 400 mu M. 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 2x200 mg dose regimen. It is concluded that following therapeutic doses of ibuprofen, the metabolism of anandamide may be affected.