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Research ArticleArticle

Unique Metabolic Pathway of [14C]Lenvatinib after Oral Administration to Male Cynomolgus Monkey

Kazuko Inoue, Naoki Asai, Hitoshi Mizuo, Katsuyuki Fukuda, Kazutomi Kusano and Tsutomu Yoshimura
Drug Metabolism and Disposition April 2012, 40 (4) 662-670; DOI: https://doi.org/10.1124/dmd.111.043281
Kazuko Inoue
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Naoki Asai
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Hitoshi Mizuo
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Katsuyuki Fukuda
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Kazutomi Kusano
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Tsutomu Yoshimura
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Abstract

Lenvatinib, a potent inhibitor of multiple tyrosine kinases, including vascular endothelial growth factor receptors 2 and 3, generated unique metabolites after oral administration of [14C]lenvatinib (30 mg/kg) to a male cynomolgus monkey. Lenvatinib was found to be transformed to a GSH conjugate, through displacement of an O-aryl moiety, at the quinoline part of the molecule in the liver and kidneys. The GSH conjugate underwent further hydrolysis by γ-glutamyltranspeptidase and dipeptidases, followed by intramolecular rearrangement, to form N-cysteinyl quinoline derivatives, which were dimerized to form disulfide dimers and also formed an N,S-cysteinyl diquinoline derivative. In urine, a thioacetic acid conjugate of the quinoline was also observed as one of the major metabolites of lenvatinib. Lenvatinib is a 4-O-aryl quinoline derivative, and such compounds have been known to undergo conjugation with GSH, accompanied by release of the O-aryl moiety. Because of intramolecular rearrangement in the case of lenvatinib, hydrolysis of the GSH conjugate yielded N-cysteinylglycine and N-cysteine conjugates instead of the corresponding S-conjugates. Because the N-substituted derivatives possess free sulfhydryl groups, dimerization through disulfide bonds and another nucleophilic substitution reaction with lenvatinib resulted in the formation of disulfanyl dimers and an N,S-cysteinyl diquinoline derivative, respectively. Characteristic product ions at m/z 235 and m/z 244, which were associated with thioquinoline and N-ethylquinoline derivatives, respectively, were used to differentiate S- and N-derivatives in this study. On the basis of accurate mass and NMR measurements, a unique metabolic pathway for lenvatinib in monkey and the proposed formation mechanism have been elucidated.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.043281.

  • ABBREVIATIONS:

    VEGF
    vascular endothelial growth factor
    LC
    liquid chromatography
    MS
    mass spectrometry
    NAC
    N-acetylcysteine
    γ-GTP
    γ-glutamyltranspeptidase
    DP
    dipeptidase
    NOESY
    nuclear Overhauser effect spectroscopy
    HPLC
    high-performance liquid chromatography
    UPLC
    ultraperformance liquid chromatography
    AMG 458
    1-(2-hydroxy-2-methylpropyl)-N-[5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
    P450
    cytochrome P450.

  • Received October 18, 2011.
  • Accepted December 29, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
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Research ArticleArticle

METABOLITES OF LENVATINIB IN CYNOMOLGUS MONKEY

Kazuko Inoue, Naoki Asai, Hitoshi Mizuo, Katsuyuki Fukuda, Kazutomi Kusano and Tsutomu Yoshimura
Drug Metabolism and Disposition April 1, 2012, 40 (4) 662-670; DOI: https://doi.org/10.1124/dmd.111.043281

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Research ArticleArticle

METABOLITES OF LENVATINIB IN CYNOMOLGUS MONKEY

Kazuko Inoue, Naoki Asai, Hitoshi Mizuo, Katsuyuki Fukuda, Kazutomi Kusano and Tsutomu Yoshimura
Drug Metabolism and Disposition April 1, 2012, 40 (4) 662-670; DOI: https://doi.org/10.1124/dmd.111.043281
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