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 approximately 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 approximately 2-3 times more potent than the S(+)-enantiomer, IC50 values of 230 and 750 microM, 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 IC50 values of 50, 440, and 80 microM being found for the R-, S-, and R,S-forms, respectively. The IC50 value for R-flurbiprofen (60 microM) was similar to the IC50 value for the S-enantiomer (50 microM). 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.
Fowler
C J
CJ
Department of Pharmacology, Umeå University, Sweden. cf@pharm.umu.se
Janson
U
U
Johnson
R M
RM
Wahlström
G
G
Stenström
A
A
Norström
K
K
Tiger
G
G
D000375:Aging; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002457:Cell Extracts; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000494:pharmacology*; D005910:Glioma; D006868:Hydrolysis / Q000187:drug effects; D007052:Ibuprofen / Q000031:analogs & derivatives / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020910:Ketorolac; D007700:Kinetics; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013997:Time Factors; D014046:Tolmetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured