In vitro metabolism of the mammalian soluble epoxide hydrolase inhibitor, 1-cyclohexyl-3-dodecyl-urea

Takaho Watanabe, Christophe Morisseau, John W. Newman, Bruce D. Hammock

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The metabolism of the soluble epoxide hydrolase (sEH) inhibitor, 1-cyclohexyl-3-dodecyl-urea (CDU), was studied in rat and human hepatic microsomes. The microsomal metabolism of CDU enhanced sEH inhibition potency of the reaction mixture and resulted in the formation of several metabolites. During the course of this study, a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry analytical method was developed to investigate simultaneously the production of these metabolites. In both rat and human hepatic microsomes, CDU was ultimately transformed into the corresponding ω-carboxylate; however, the rodent tissue appeared to perform this transformation more rapidly. After a 60-min incubation in rat hepatic microsomes, the percentage of residual CDU, the ω-carboxylate, and the intermediary ω-hydroxyl were about 20%, 20%, and 50%, respectively. Carbon monooxide inhibited the metabolism of CDU by rat hepatic microsomes, suggesting that the initial step is catalyzed by cytochrome P450. Further metabolism was enhanced by the addition of NAD, suggesting that dehydrogenases are associated with intermediate metabolic steps. Regardless, the ultimate product of microsomal metabolism, 12-(3-cyclohexyl-ureido)-dodecanoic acid, is also an excellent sEH inhibitor with several hundred-fold higher solubility, supporting the hypothesis that CDU has prodrug characteristics. These findings will facilitate the rational design and optimization of sEH inhibitors with better physical properties and improved metabolic stability.

Original languageEnglish (US)
Pages (from-to)846-853
Number of pages8
JournalDrug Metabolism and Disposition
Volume31
Issue number7
DOIs
StatePublished - Jul 1 2003

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Epoxide Hydrolases
Metabolism
Microsomes
Rats
lauric acid
Liver
Metabolites
Enzyme inhibition
Prodrugs
High performance liquid chromatography
Tandem Mass Spectrometry
Hydroxyl Radical
NAD
Solubility
Cytochrome P-450 Enzyme System
Mass spectrometry
1-cyclohexyl-3-dodecylurea
In Vitro Techniques
Rodentia
Oxidoreductases

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

In vitro metabolism of the mammalian soluble epoxide hydrolase inhibitor, 1-cyclohexyl-3-dodecyl-urea. / Watanabe, Takaho; Morisseau, Christophe; Newman, John W.; Hammock, Bruce D.

In: Drug Metabolism and Disposition, Vol. 31, No. 7, 01.07.2003, p. 846-853.

Research output: Contribution to journalArticle

Watanabe, Takaho ; Morisseau, Christophe ; Newman, John W. ; Hammock, Bruce D. / In vitro metabolism of the mammalian soluble epoxide hydrolase inhibitor, 1-cyclohexyl-3-dodecyl-urea. In: Drug Metabolism and Disposition. 2003 ; Vol. 31, No. 7. pp. 846-853.
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