Open AccessPharmacokinetics, pharmacodynamics and safety studies on URB 937, a peripherally restricted fatty acid amide hydrolase inhibitor, in rats
Author(s) -
Vozella Valentina,
Ahmed Faizy,
Choobchian Paoula,
Merrill Collin B.,
Zibardi Cristina,
Tarzia Giorgio,
Mor Marco,
Duranti Andrea,
Tontini Andrea,
Rivara Silvia,
Piomelli Daniele
Publication year - 2019
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.13166
Subject(s) - fatty acid amide hydrolase , tolerability , pharmacokinetics , pharmacology , pharmacodynamics , oral administration , endocannabinoid system , anandamide , chemistry , medicine , adverse effect , biochemistry , antagonist , cannabinoid receptor , receptor
Objectives URB 937, a peripheral fatty acid amide hydrolase ( FAAH ) inhibitor, exerts profound analgesic effects in animal models. We examined, in rats, (1) the pharmacokinetic profile of oral URB 937; (2) the compound's ability to elevate levels of the representative FAAH substrate, oleoylethanolamide ( OEA ); and (3) the compound's tolerability after oral administration. Methods We developed a liquid chromatography/tandem mass spectrometry ( LC / MS ‐ MS ) method to measure URB 937 and used a pre‐existing LC / MS ‐ MS assay to quantify OEA . FAAH activity was measured using a radioactive substrate. The tolerability of single or repeated (once daily for 2 weeks) oral administration of supramaximal doses of URB 937 (100, 300, 1000 mg/kg) was assessed by monitoring food intake, water intake and body weight, followed by post‐mortem evaluation of organ structure. Key findings URB 937 was orally available in male rats ( F = 36%), but remained undetectable in brain when administered at doses that maximally inhibit FAAH activity and elevate OEA in plasma and liver. Acute and subchronic treatment with high doses of URB 937 was well‐tolerated and resulted in FAAH inhibition in brain. Conclusions Pain remains a major unmet medical need. The favourable pharmacokinetic and pharmacodynamic properties of URB 937, along with its tolerability, encourage further development studies on this compound.