Tags

Type your tag names separated by a space and hit enter

Pharmacokinetics, pharmacodynamics and safety studies on URB937, a peripherally restricted fatty acid amide hydrolase inhibitor, in rats.
J Pharm Pharmacol 2019; 71(12):1762-1773JP

Abstract

OBJECTIVES

URB937, 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 URB937; (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 URB937 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 URB937 (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

URB937 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 URB937 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 URB937, along with its tolerability, encourage further development studies on this compound.

Authors+Show Affiliations

Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA.Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA.Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA.Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA.Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA.Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.Department of Food and Drug, University of Parma, Parma, Italy.Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.Department of Food and Drug, University of Parma, Parma, Italy.Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA, USA. Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA. Center for the Study of Cannabis, University of California, Irvine, Irvine, CA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31579946

Citation

Vozella, Valentina, et al. "Pharmacokinetics, Pharmacodynamics and Safety Studies On URB937, a Peripherally Restricted Fatty Acid Amide Hydrolase Inhibitor, in Rats." The Journal of Pharmacy and Pharmacology, vol. 71, no. 12, 2019, pp. 1762-1773.
Vozella V, Ahmed F, Choobchian P, et al. Pharmacokinetics, pharmacodynamics and safety studies on URB937, a peripherally restricted fatty acid amide hydrolase inhibitor, in rats. J Pharm Pharmacol. 2019;71(12):1762-1773.
Vozella, V., Ahmed, F., Choobchian, P., Merrill, C. B., Zibardi, C., Tarzia, G., ... Piomelli, D. (2019). Pharmacokinetics, pharmacodynamics and safety studies on URB937, a peripherally restricted fatty acid amide hydrolase inhibitor, in rats. The Journal of Pharmacy and Pharmacology, 71(12), pp. 1762-1773. doi:10.1111/jphp.13166.
Vozella V, et al. Pharmacokinetics, Pharmacodynamics and Safety Studies On URB937, a Peripherally Restricted Fatty Acid Amide Hydrolase Inhibitor, in Rats. J Pharm Pharmacol. 2019;71(12):1762-1773. PubMed PMID: 31579946.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics, pharmacodynamics and safety studies on URB937, a peripherally restricted fatty acid amide hydrolase inhibitor, in rats. AU - Vozella,Valentina, AU - Ahmed,Faizy, AU - Choobchian,Paoula, AU - Merrill,Collin B, AU - Zibardi,Cristina, AU - Tarzia,Giorgio, AU - Mor,Marco, AU - Duranti,Andrea, AU - Tontini,Andrea, AU - Rivara,Silvia, AU - Piomelli,Daniele, Y1 - 2019/10/03/ PY - 2019/06/27/received PY - 2019/09/01/accepted PY - 2020/12/01/pmc-release PY - 2019/10/4/pubmed PY - 2019/10/4/medline PY - 2019/10/4/entrez KW - URB937 KW - analgesia KW - endocannabinoid KW - fatty acid amide hydrolase KW - oleoylethanolamide SP - 1762 EP - 1773 JF - The Journal of pharmacy and pharmacology JO - J. Pharm. Pharmacol. VL - 71 IS - 12 N2 - OBJECTIVES: URB937, 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 URB937; (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 URB937 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 URB937 (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: URB937 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 URB937 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 URB937, along with its tolerability, encourage further development studies on this compound. SN - 2042-7158 UR - https://www.unboundmedicine.com/medline/citation/31579946/Pharmacokinetics_pharmacodynamics_and_safety_studies_on_URB937_a_peripherally_restricted_fatty_acid_amide_hydrolase_inhibitor_in_rats_ L2 - https://doi.org/10.1111/jphp.13166 DB - PRIME DP - Unbound Medicine ER -