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Tytuł:
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Identification of the metabolites of XL092 in rat and human by using ultra-high performance liquid chromatography high resolution mass spectrometry.
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Autorzy:
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Yuan L; Department of Pharmacy, Suining Central Hospital, No. 127 West Desheng Road, Chuanshan District, Suining 629000, Sichuan Province, China. Electronic address: biopharm_.
Li J; Department of Pharmacy, Suining Central Hospital, No. 127 West Desheng Road, Chuanshan District, Suining 629000, Sichuan Province, China.
Feng M; Department of Pharmacy, Suining Central Hospital, No. 127 West Desheng Road, Chuanshan District, Suining 629000, Sichuan Province, China.
Zou XR; Department of Pharmacy, Suining Central Hospital, No. 127 West Desheng Road, Chuanshan District, Suining 629000, Sichuan Province, China.
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Źródło:
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Journal of pharmaceutical and biomedical analysis [J Pharm Biomed Anal] 2021 Nov 30; Vol. 206, pp. 114390. Date of Electronic Publication: 2021 Sep 22.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: <2006->: London : Elsevier Science
Original Publication: Oxford ; New York : Pergamon Press, c1983-
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MeSH Terms:
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Microsomes, Liver*/metabolism
Tandem Mass Spectrometry*
Animals ; Chromatography, High Pressure Liquid ; Humans ; Hydroxylation ; Protein Kinase Inhibitors/metabolism ; Rats
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Contributed Indexing:
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Keywords: Metabolic pathways; Metabolite identification; Tyrosine kinase inhibitor; XL092
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Substance Nomenclature:
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0 (Protein Kinase Inhibitors)
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Entry Date(s):
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Date Created: 20211002 Date Completed: 20211013 Latest Revision: 20211013
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Update Code:
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20240105
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DOI:
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10.1016/j.jpba.2021.114390
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PMID:
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34600174
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XL092 is a novel tyrosine kinase inhibitor with antitumor activity. The goal of this study was to evaluate its in vitro metabolism of XL092 using rat and human liver microsomes and hepatocytes. The metabolites were identified using ultra-high performance liquid chromatography combined with high resolution mass spectrometry. The structure of the metabolite was characterized by accurate mass, elemental composition and MS/MS spectra. The cytochrome P450 enzyme responsible for XL092 metabolism was evaluated by using recombinant human CYP450 enzymes. A total of 26 metabolites, including 21 phase I metabolites and 5 phase II metabolites, were characterized. XL092 was metabolized mainly through oxidative defluorination, hydroxylation, N-demethylation, O-demethylation, amide hydrolysis, N-dealkylation, O-dealkylation, N-oxygenation and glucuronidation. Among these metabolites, M10 (oxidative defluorination) and M17 (hydroxylation) were the most abundant metabolites. CYP3A4 and CYP2D6 were the major enzymes responsible for XL092 metabolism. Taken together, this study for the first time evaluated the in vitro metabolic profiles of XL092 in rat and human, which is of great help for us to investigate the XL092 pharmacokinetic and toxicity assessment and to predict the in vivo human metabolism.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021. Published by Elsevier B.V.)
