In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors.
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.
Center for Nephrology and Clinical Metabolomics, Division of Nephrology and Rheumatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 210072, PR China; Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
Jun-Yan
JY
Liu
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
Hsing-Ju
HJ
Tsai
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
Christophe
C
Morisseau
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
Jozsef
J
Lango
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
Sung Hee
SH
Hwang
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
Takaho
T
Watanabe
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
In-Hae
IH
Kim
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA. Electronic address: bdhammock@ucdavis.edu.
Bruce D
BD
Hammock
D000218:Adamantane / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014508:Urea / Q000378:metabolism* / Q000494:pharmacology
D014508:Urea; D004851:Epoxide Hydrolases; D000218:Adamantane
Cytochrome P450s; Drug metabolism; LC–MS/MS; NMR; Soluble epoxide hydrolase