title: Roles of UGT, P450, and Gut Microbiota in the Metabolism of Epacadostat in Humans.
abstract: Epacadostat (EPA, INCB024360) is a first-in-class, orally active, investigational drug targeting the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In Phase I studies, EPA has demonstrated promising clinical activity when used in combination with checkpoint modulators. When the metabolism of EPA was investigated in humans, three major, IDO1-inactive, circulating plasma metabolites were detected and characterized: M9, a direct O-glucuronide of EPA; M11, an amidine; and M12, N-dealkylated M11. Glucuronidation of EPA to form M9 is the dominant metabolic pathway, and in vitro, this metabolite is formed by UGT1A9. However, negligible quantities of M11 and M12 were detected when EPA was incubated with a panel of human microsomes from multiple tissues, hepatocytes, recombinant human cytochrome P450s (P450s), and non-P450 enzymatic systems. Given the reductive nature of M11 formation and the inability to define its source, the role of gut microbiota was investigated. Analysis of plasma from mice dosed with EPA following pretreatment with either antibiotic (ciprofloxacin) to inhibit gut bacteria or 1-aminobenzotriazole (ABT) to systemically inhibit P450s demonstrated that gut microbiota is responsible for the formation of M11. Incubations of EPA in human feces confirmed the role of gut bacteria in the formation of M11. Further, incubations of M11 with recombinant P450s showed that M12 is formed via N-dealkylation of M11 by CYP3A4, CYP2C19, and CYP1A2. Thus, in humans three major plasma metabolites of EPA were characterized: two primary metabolites, M9 and M11, formed directly from EPA via UGT1A9 and gut microbiota, respectively, and M12 formed as a secondary metabolite via P450s from M11.
authors.affiliation: Incyte Corporation, Wilmington, Delaware jboer@incyte.com.
authors.forename: Jason
authors.initials: J
authors.lastname: Boer
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Ruth
authors.initials: R
authors.lastname: Young-Sciame
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Fiona
authors.initials: F
authors.lastname: Lee
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Bowman
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yang
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Jack G
authors.initials: JG
authors.lastname: Shi
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Nedza
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: William
authors.initials: W
authors.lastname: Frietze
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Laurine
authors.initials: L
authors.lastname: Galya
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Combs
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Swamy
authors.initials: S
authors.lastname: Yeleswaram
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D064307:Microbiota; D010091:Oximes / Q000378:metabolism*; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013449:Sulfonamides / Q000378:metabolism*; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D010091:Oximes; D013449:Sulfonamides; C000715591:UGT1A9 protein, human; C000715592:Ugt1a9 protein, mouse; C000613752:epacadostat; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9