In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors

Jun Yan Liu, Hsing Ju Tsai, Christophe Morisseau, Jozsef Lango, Sung Hee Hwang, Takaho Watanabe, In Hae Kim, Bruce D. Hammock

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

N,N′-disubstituted urea-based soluble epoxide hydrolase (sEH) inhibitors are promising therapeutics for hypertension, inflammation, and pain in multiple animal models. The drug absorption and pharmacological efficacy of these inhibitors have been reported extensively. However, the drug metabolism of these inhibitors is not well described. Here we reported the metabolic profile and associated biochemical studies of an N-adamantyl urea-based sEH inhibitor 1-adamantan-1-yl-3-(5-(2-(2-ethoxyethoxy)ethoxy)pentyl)urea (AEPU) in vitro and in vivo. The metabolites of AEPU were identified by interpretation of liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and/or NMR. In vitro, AEPU had three major positions for phase I metabolism including oxidations on the adamantyl moiety, urea nitrogen atoms, and cleavage of the polyethylene glycol chain. In a rodent model, the metabolites from the hydroxylation on the adamantyl group and nitrogen atom were existed in blood while the metabolites from cleavage of polyethylene glycol chain were not found in urine. The major metabolite found in rodent urine was 3-(3-adamantyl-ureido)-propanoic acid, a presumably from cleavage and oxidation of the polyethylene glycol moiety. All the metabolites found were active but less potent than AEPU at inhibiting human sEH. Furthermore, cytochrome P450 (CYP) 3A4 was found to be a major enzyme mediating AEPU metabolism. In conclusion, the metabolism of AEPU resulted from oxidation by CYP could be shared with other N-adamantyl-urea-based compounds. These findings suggest possible therapeutic roles for AEPU and new strategies for drug design in this series of possible drugs.

Original languageEnglish (US)
Pages (from-to)718-731
Number of pages14
JournalBiochemical Pharmacology
Volume98
Issue number4
DOIs
StatePublished - Dec 15 2015

Keywords

  • Cytochrome P450s
  • Drug metabolism
  • LC-MS/MS
  • NMR
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

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    Liu, J. Y., Tsai, H. J., Morisseau, C., Lango, J., Hwang, S. H., Watanabe, T., Kim, I. H., & Hammock, B. D. (2015). In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors. Biochemical Pharmacology, 98(4), 718-731. https://doi.org/10.1016/j.bcp.2015.10.013