In vitro and in vivo Metabolism of a Potent Inhibitor of Soluble Epoxide Hydrolase, 1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea

• Published in: Frontiers in pharmacology 2019-05, Vol.10, p.464-464
• Main Authors: Wan, Debin, Yang, Jun, McReynolds, Cindy B, Barnych, Bogdan, Wagner, Karen M, Morisseau, Christophe, Hwang, Sung Hee, Sun, Jia, Blöcher, René, Hammock, Bruce D
• Format: Article
• Language: English
• Subjects: drug metabolism; in vitro; in vivo; LC-MS; Pharmacology; soluble epoxide hydrolase inhibitor; TPPU
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2019.00464

1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (TPPU) is a potent soluble epoxide hydrolase (sEH) inhibitor that is used extensively in research for modulating inflammation and protecting against hypertension, neuropathic pain, and neurodegeneration. Despite its wide use in various animal disease models, the metabolism of TPPU has not been well-studied. A broader understanding of its metabolism is critical for determining contributions of metabolites to the overall safety and effectiveness of TPPU. Herein, we describe the identification of TPPU metabolites using LC-MS/MS strategies. Four metabolites of TPPU (M1-M4) were identified from rat urine by a sensitive and specific LC-MS/MS method with double precursor ion scans. Their structures were further supported by LC-MS/MS comparison with synthesized standards. Metabolites M1 and M2 were formed from hydroxylation on a propionyl group of TPPU; M3 was formed by amide hydrolysis of the 1-propionylpiperdinyl group on TPPU; and M4 was formed by further oxidation of the hydroxylated metabolite M2. Interestingly, the predicted α-keto amide metabolite and 4-(trifluoromethoxy)aniline (metabolite from urea cleavage) were not detected by the LC-MRM-MS method. This indicates that if formed, the two potential metabolites represent