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Research ArticleArticle

Investigations of Hydrazine Cleavage of Eltrombopag in Humans

Yanli Deng, Martin Rogers, Caroline Sychterz, Kimberly Talley, Yanwen Qian, David Bershas, May Ho, Wei Shi, Emile P. Chen, Cosette Serabjit-Singh and Peter D. Gorycki
Drug Metabolism and Disposition September 2011, 39 (9) 1747-1754; DOI: https://doi.org/10.1124/dmd.111.040188
Yanli Deng
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Martin Rogers
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Caroline Sychterz
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Kimberly Talley
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Yanwen Qian
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David Bershas
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May Ho
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Wei Shi
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Emile P. Chen
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Cosette Serabjit-Singh
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Peter D. Gorycki
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Abstract

After oral administration to humans, eltrombopag undergoes extensive cleavage of its hydrazine linkage to metabolites, which are exclusively eliminated in urine. In vitro, the cleavage pathway was not detected in systems using cytochrome P450 enzymes, renal or hepatic microsomes, or hepatocytes but was readily evident after anaerobic incubation with rodent cecal contents or human fecal homogenate. Antibiotic treatment in vitro and in vivo inhibited eltrombopag cleavage, further indicating that cleavage is via gut microbes. Antibiotic treatment did not alter the systemic exposure of eltrombopag in mice. Oral and intravenous pharmacokinetic characterization in the mice with one of the cleavage products indicated that it was readily absorbed, conjugated, and eliminated in urine, consistent with its fate after oral administration of eltrombopag. Variation in this microbial pathway, for example by antibiotic cotherapy, is unlikely to be clinically significant.

Footnotes

  • This work was supported by GlaxoSmithKline.

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

    doi:10.1124/dmd.111.040188.

  • ABBREVIATIONS:

    SB-611855
    2′-hydroxy-3′-amino-3-biphenylcarboxylic acid
    HPLC
    high-performance liquid chromatography
    DMSO
    dimethyl sulfoxide
    LC
    liquid chromatography
    MS
    mass spectrometry
    MRM
    multiple reaction monitoring
    MS/MS
    tandem mass spectrometry
    AUC
    area under the composite plasma concentration-time curve
    OR-1855
    (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one.

  • Received April 19, 2011.
  • Accepted June 6, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (9)
Drug Metabolism and Disposition
Vol. 39, Issue 9
1 Sep 2011
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Research ArticleArticle

Investigations of Hydrazine Cleavage of Eltrombopag in Humans

Yanli Deng, Martin Rogers, Caroline Sychterz, Kimberly Talley, Yanwen Qian, David Bershas, May Ho, Wei Shi, Emile P. Chen, Cosette Serabjit-Singh and Peter D. Gorycki
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1747-1754; DOI: https://doi.org/10.1124/dmd.111.040188

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Research ArticleArticle

Investigations of Hydrazine Cleavage of Eltrombopag in Humans

Yanli Deng, Martin Rogers, Caroline Sychterz, Kimberly Talley, Yanwen Qian, David Bershas, May Ho, Wei Shi, Emile P. Chen, Cosette Serabjit-Singh and Peter D. Gorycki
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1747-1754; DOI: https://doi.org/10.1124/dmd.111.040188
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