title: Metabolite elucidation of the Hsp90 inhibitor SNX-2112 using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS).
abstract: 1. The novel heat-shock protein 90 inhibitor SNX-2112 is a promising drug candidate for treating various types of cancers. Here we aim to determine the metabolic pathways of SNX-2112 in rats in vivo and in humans in vitro. 2. Metabolite identification was performed using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method. In vitro metabolism studies were performed using liver and intestine microsomes, as well as recombinant human cytochrome P450 (CYP) enzymes. 3. Analysis of rat plasma, urine, and feces revealed a total of eight metabolites, one reductive metabolite (M1), one structurally unknown metabolite (M2), and six mono-oxidative metabolites (M3-1, M3-2, M3-3, M3-4, M3-5, and M3-6). The reduction, M2, and mono-oxidation pathways were responsible for 0.8 ± 0.3 %, 18.3 ± 9.1 %, and 39.4% ± 6.1 of SNX-2112 clearance from rats, respectively. 4. SNX-2112 was subjected to the same types of metabolism in human liver and intestine microsomes. Reaction phenotyping showed that CYP3A4, 3A5, 2D6, and 1A1 were mainly responsible for SNX-2112 metabolism. 5.  In conclusion, we have elucidated the metabolic pathways of SNX-2112 and highlighted that metabolism was the predominant pathway for its clearance. Better understanding of SNX-2112 metabolism should facilitate the drug development of this promising anti-cancer agent.
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, Jinan University , West, Guangzhou , China and.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Hongming
authors.initials: H
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.forename: Dong
authors.initials: D
authors.lastname: Dong
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Ma
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
authors.forename: Baojian
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D005243:Feces; D006576:Heterocyclic Compounds, 4 or More Rings / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D008658:Inactivation, Metabolic; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D013058:Mass Spectrometry / Q000379:methods*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; C534922:SNX 2112; D003577:Cytochrome P-450 Enzyme System; C569463:CYP1A1 protein, human; C110332:CYP2F1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019389:Cytochrome P-450 CYP2D6; D000072467:Cytochrome P450 Family 2