Inhibition of Anandamide Hydrolysis by the Enantiomers of Ibuprofen, Ketorolac, and Flurbiprofen

The endogenous cannabimimetic anandamide is hydrolyzed by a fatty acid amide hydrolase to yield arachidonic acid and ethanolamine. In the present study, the regional distribution of the activity and its sensitivity to inhibition by the enantiomers of ibuprofen, ketorolac, and flurbiprofen has been investigated. The rate of [3H]anandamide hydrolysis was found in both 7-week-old and 90-week-old rats to be in the order hippocampus > cerebral cortex > cerebellum > striatum ≈ midbrain, with higher rates of hydrolysis for the 7-week-old rats than for the 90-week-old rats. In whole brain (minus cerebellum), the R(−)-enantiomer of ibuprofen was a mixed-type inhibitor of anandamide hydrolysis and was ∼2–3 times more potent than the S(+)-enantiomer, IC50values of 230 and 750 μM, respectively, being found. A similar pattern of inhibition of anandamide hydrolysis was seen when intact C6 rat glioma cells were used. Ketorolac inhibited rat brain anandamide hydrolysis, with IC50values of 50, 440, and 80 μM being found for the R-, S-, and R,S-forms, respectively. The IC50value for R-flurbiprofen (60 μM) was similar to the IC50value for the S-enantiomer (50 μM). These data demonstrate that there is no dramatic enantiomeric selectivity of NSAID compounds as inhibitors of fatty acid amide hydrolase enzyme(s) responsible for the hydrolysis of anandamide. The enantiomers of flurbiprofen and R-ketorolac are the most potent NSAID inhibitors of fatty acid amide hydrolase yet reported.