IBUPROFEN INHIBITS THE METABOLISM OF THE ENDOGENOUS CANNABIMIMETIC AGENT ANANDAMIDE

A measure of the metabolism of anandamide, an endogenous cannabimimeti c agent, by rat cerebellar membrane preparations was obtained by follo wing 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, incubatio n 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 a nandamide metabolism during the binding assay) produced 57+/-3, 38+/-5 and 19+/-7 % inhibition, respectively, of [3H]WIN 55212-2 binding. Th is time-dependent effect was blocked by ibuprofen but not by acetyl sa licylic 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 val ue for ibuprofen of similar to 400 mu M. The potency of ibuprofen as a n inhibitor of anandamide metabolism was of the same order of magnitud e as required for inhibition of cyclooxygenase-2 in cell-free systems and of the peak plasma concentrations of this drug following a 2x200 m g dose regimen. It is concluded that following therapeutic doses of ib uprofen, the metabolism of anandamide may be affected.