RT Journal Article
SR Electronic
T1 IN VITRO METABOLISM OF THE MAMMALIAN SOLUBLE EPOXIDE HYDROLASE INHIBITOR, 1-CYCLOHEXYL-3-DODECYL-UREA
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 846
OP 853
DO 10.1124/dmd.31.7.846
VO 31
IS 7
A1 Takaho Watanabe
A1 Christophe Morisseau
A1 John W. Newman
A1 Bruce D. Hammock
YR 2003
UL http://dmd.aspetjournals.org/content/31/7/846.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics