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Research ArticleArticle

Metabolism of Flumatinib, a Novel Antineoplastic Tyrosine Kinase Inhibitor, in Chronic Myelogenous Leukemia Patients

Aishen Gong, Xiaoyan Chen, Pan Deng and Dafang Zhong
Drug Metabolism and Disposition August 2010, 38 (8) 1328-1340; DOI: https://doi.org/10.1124/dmd.110.032326
Aishen Gong
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Xiaoyan Chen
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Pan Deng
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Dafang Zhong
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Abstract

4-(4-Methyl-piperazin-1-ylmethyl)-N-[6-methyl-5-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pyridin-3-yl]-3-trifluoromethyl-benzamide (flumatinib, HH-GV678), an antineoplastic tyrosine kinase inhibitor, is currently in Phase I clinical trials in China for the treatment of chronic myelogenous leukemia (CML). The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways of flumatinib in humans after oral administration. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 34 metabolites; 7 primary metabolites were confirmed by comparison with synthetic reference standards. The results show that the parent drug flumatinib was the main form recovered in human plasma, urine, and feces. The main metabolites of flumatinib in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis. In addition to these phase I metabolites, several phase II glucuronidation and acetylation products were detected in plasma, urine, and feces. The observed circulating metabolites included an N-demethylated metabolite (M1), two hydrolytic metabolites (M3, M4), oxidation metabolites (M2-1, M2-4, M2-7, M2-9, and M14), a glucuronide conjugate (M16-2), and several multiple metabolic products. Flumatinib was predominantly metabolized by amide bond cleavage to yield two corresponding hydrolytic products. By comparison with the related drug 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib), we concluded that the electron-withdrawing groups of trifluoromethyl and pyridine facilitated the amide bond cleavage and led to the in vivo formation of a carboxylic acid and an amine.

Footnotes

  • This work was supported by the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program,” China [Grant 2009ZX09301-001].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.032326.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CML
    chronic myelogenous leukemia
    imatinib
    4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide
    flumatinib/HH-GV678
    4-(4-methyl-piperazin-1-ylmethyl)-N-[6-methyl-5-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pyridin-3-yl]-3-trifluoromethyl-benzamide
    UPLC
    ultra-performance liquid chromatography
    Q-TOF MS
    quadrupole time-of-flight mass spectrometer
    ESI
    electrospray ionization
    CE
    collision energy
    DMSO
    dimethyl sulfoxide.

  • Received January 18, 2010.
  • Accepted May 17, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (8)
Drug Metabolism and Disposition
Vol. 38, Issue 8
1 Aug 2010
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Research ArticleArticle

Metabolism of Flumatinib, a Novel Antineoplastic Tyrosine Kinase Inhibitor, in Chronic Myelogenous Leukemia Patients

Aishen Gong, Xiaoyan Chen, Pan Deng and Dafang Zhong
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1328-1340; DOI: https://doi.org/10.1124/dmd.110.032326

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Research ArticleArticle

Metabolism of Flumatinib, a Novel Antineoplastic Tyrosine Kinase Inhibitor, in Chronic Myelogenous Leukemia Patients

Aishen Gong, Xiaoyan Chen, Pan Deng and Dafang Zhong
Drug Metabolism and Disposition August 1, 2010, 38 (8) 1328-1340; DOI: https://doi.org/10.1124/dmd.110.032326
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