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Research ArticleArticle

In Vitro Metabolism of BIIB021, an Inhibitor of Heat Shock Protein 90, in Liver Microsomes and Hepatocytes of Rats, Dogs, and Humans and Recombinant Human Cytochrome P450 Isoforms

Lin Xu, Caroline Woodward, Samina Khan and Chandra Prakash
Drug Metabolism and Disposition April 2012, 40 (4) 680-693; DOI: https://doi.org/10.1124/dmd.111.043000
Lin Xu
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Caroline Woodward
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Samina Khan
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Chandra Prakash
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Abstract

Inhibition of heat shock protein 90 (HSP90) results in the degradation of oncoproteins that drive malignant progression and induce cell death, thus making HSP90 a potential target of cancer therapy. 6-Chloro-9-(4-methoxy-3, 5-dimethyl-pyridin-2-ylmethyl)-9H-purin-2-ylamine (BIIB021), a synthetic HSP90 inhibitor, exhibited promising antitumor activity in preclinical models. It is currently in phase II clinical trials for the oral treatment of breast cancer. The objective of this study was to obtain both quantitative and qualitative metabolic profiles of [14C]BIIB021 in rat, dog, and human liver microsomes and hepatocytes to provide support for in vivo safety and clinical studies. The metabolites of [14C]BIIB021 were identified using liquid chromatography-tandem mass spectrometry coupled with radiometric detection. BIIB021 was extensively metabolized in both liver microsomes and hepatocytes. The major oxidative metabolic pathways identified for all species were due to hydroxylation (M7) and O-demethylation (M2) of the methoxy-dimethylpyridine moiety. The majority of M7 in dog hepatocytes was further conjugated to form the glucuronide (M4). Oxidative dechlorination (M6), monooxygenation (M10), and oxidative N-dealkylation of the methoxy-dimethylpyridine moiety (M11 and M12) were observed as the minor metabolic pathways in hepatocytes of all three species. A glutathione conjugate (M18) was also identified in all species. Its formation was catalyzed, in part, by soluble glutathione transferase via direct displacement of the chlorine on the amino-chloropurine moiety. Subsequent minor secondary metabolites M13, M14, M15, and M17 were observed in human, dog, and rat hepatocytes. Results from incubations of BIIB021 with human recombinant cytochrome P450 (P450) isoforms and a P450 antibody inhibition study in human liver microsomes suggested that the formation of M7 is mainly catalyzed by CYP2C19 and CYP3A4, whereas the formation of minor metabolite M2 in human liver microsomes probably could be attributed to CYP3A4.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.043000.

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

  • ABBREVIATIONS:

    HSP
    heat shock protein
    LC
    liquid chromatography
    BIIB021
    6-chloro-9-(4-methoxy-3,5-dimethylpyridin-2-yl)methyl-9H-purin-2-ylamine
    MS/MS
    tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    MS
    mass spectrometry
    P450
    cytochrome P450
    AO
    aldehyde oxidase
    GSH
    glutathione
    CF2246
    2-((2-amino-6-chloro-9H-purin-9-yl)methyl)-3,5-dimethylpyridin-4-ol
    5-hydroxymethyl-BIIB021 glucuronide
    5-hydroxymethyl glucuronide
    CF3785
    (6-((2-amino-6-chloro-9H-purin-9-yl)methyl)-4-methoxy-5-methylpyridin-3-yl)methanol
    CF2483
    2-amino-6-chloro-9-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-8-ol
    LM
    liver microsomes
    RAM
    radioactivity monitor
    HRMS
    high-resolution mass spectrometry.

  • Received September 26, 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

METABOLISM OF A PYRIDINYLMETHYL-9H-PURIN-2-YLAMINE ANALOG

Lin Xu, Caroline Woodward, Samina Khan and Chandra Prakash
Drug Metabolism and Disposition April 1, 2012, 40 (4) 680-693; DOI: https://doi.org/10.1124/dmd.111.043000

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Research ArticleArticle

METABOLISM OF A PYRIDINYLMETHYL-9H-PURIN-2-YLAMINE ANALOG

Lin Xu, Caroline Woodward, Samina Khan and Chandra Prakash
Drug Metabolism and Disposition April 1, 2012, 40 (4) 680-693; DOI: https://doi.org/10.1124/dmd.111.043000
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