Acidic nonsteroidal anti-inflammatory drugs inhibit rat brain fatty acid amide hydrolase in a pH-dependent manner.
Previous studies have demonstrated that fatty acid amide hydrolase, the enzyme responsible for the metabolism of anandamide, is inhibited by the acidic non-steroidal anti-inflammatory drug (NSAID) ibuprofen with a potency that increases as the assay pH is reduced. Here we show that (R)-, (S)- and (R,S)-flurbiprofen, indomethacin and niflumic acid show similar pH-dependent shifts in potency to that seen with ibuprofen. Thus, (S)-flurbiprofen inhibited 2 microM [3H]anandamide metabolism with IC50 values of 13 and 50 microM at assay pH values of 6 and 8, respectively. In contrast, the neutral compound celecoxib was a weak fatty acid amide hydrolase inhibitor and showed no pH dependency (IC50 values approximately 300 microM at both assay pH). The cyclooxygenase-2-selective inhibitors nimesulide and SC-58125 did not inhibit fatty acid amide hydrolase activity at either pH. The data are consistent with the conclusion that the non-ionised forms of the acidic NSAIDs are responsible for the inhibition of fatty acid amide hydrolase.
Fowler
Christopher J
CJ
Department of Pharmacology and Clinical Neuroscience, Umeå University, SE-901 87 Umeå, Sweden. cf@pharm.umu.se
Holt
Sandra
S
Tiger
Gunnar
G
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D006863:Hydrogen-Ion Concentration; D051381:Rats; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000099252:Fatty Acid Amide Hydrolases