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Research ArticleArticle

Comparative Metabolism of 14C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans

Donglu Zhang, Kan He, Nirmala Raghavan, Lifei Wang, James Mitroka, Brad D. Maxwell, Robert M. Knabb, Charles Frost, Alan Schuster, Feng Hao, Zheming Gu, W. Griffith Humphreys and Scott J. Grossman
Drug Metabolism and Disposition August 2009, 37 (8) 1738-1748; DOI: https://doi.org/10.1124/dmd.108.025981
Donglu Zhang
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Kan He
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Nirmala Raghavan
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Lifei Wang
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James Mitroka
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Brad D. Maxwell
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Robert M. Knabb
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Charles Frost
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Alan Schuster
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Feng Hao
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Zheming Gu
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W. Griffith Humphreys
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Scott J. Grossman
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Abstract

The metabolism and disposition of [14C]apixaban, a potent, reversible, and direct inhibitor of coagulation factor Xa, were investigated in mice, rats, rabbits, dogs, and humans after a single oral administration and in incubations with hepatocytes. In plasma, the parent compound was the major circulating component in mice, rats, dogs, and humans. O-Demethyl apixaban sulfate (M1) represented approximately 25% of the parent area under the time curve in human plasma. This sulfate metabolite was present, but in lower amounts relative to the parent, in plasma from mice, rats, and dogs. Rabbits showed a plasma metabolite profile distinct from that of other species with apixaban as a minor component and M2 (O-demethyl apixaban) and M14 (O-demethyl apixaban glucuronide) as prominent components. The fecal route was a major elimination pathway, accounting for >54% of the dose in animals and >46% in humans. The urinary route accounted for <15% of the dose in animals and 25 to 28% in humans. Apixaban was the major component in feces of every species and in urine of all species except rabbit. M1 and M2 were common prominent metabolites in urine and feces of all species as well as in bile of rats and humans. In vivo metabolite profiles showed quantitative differences between species and from in vitro metabolite profiles, but all human metabolites were found in animal species. After intravenous administration of [14C]apixaban to bile duct-cannulated rats, the significant portion (approximately 22%) of the dose was recovered as parent drug in the feces, suggesting direct excretion of the drug from gastrointestinal tracts of rats. Overall, apixaban was effectively eliminated via multiple elimination pathways in animals and humans, including oxidative metabolism, and direct renal and intestinal excretion.

Footnotes

  • This work was supported by Bristol-Myers Squibb and Pfizer Inc.

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

  • doi:10.1124/dmd.108.025981.

  • ABBREVIATIONS: BDC, bile duct cannulation; BMS-562247, 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydro pyrazolo[5,4-c]pyridine-3-carboxamide; HPLC, high-performance liquid chromatography; GI, gastrointestinal; MS, mass spectrometry; LC, liquid chromatography; MS/MS, mass spectrometry; amu, atomic mass units.

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

  • ↵1 Current affiliation: UniTris Biopharma Company, Shanghai, China.

    • Accepted May 1, 2009.
    • Received December 4, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (8)
Drug Metabolism and Disposition
Vol. 37, Issue 8
1 Aug 2009
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Research ArticleArticle

Comparative Metabolism of 14C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans

Donglu Zhang, Kan He, Nirmala Raghavan, Lifei Wang, James Mitroka, Brad D. Maxwell, Robert M. Knabb, Charles Frost, Alan Schuster, Feng Hao, Zheming Gu, W. Griffith Humphreys and Scott J. Grossman
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1738-1748; DOI: https://doi.org/10.1124/dmd.108.025981

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Research ArticleArticle

Comparative Metabolism of 14C-Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans

Donglu Zhang, Kan He, Nirmala Raghavan, Lifei Wang, James Mitroka, Brad D. Maxwell, Robert M. Knabb, Charles Frost, Alan Schuster, Feng Hao, Zheming Gu, W. Griffith Humphreys and Scott J. Grossman
Drug Metabolism and Disposition August 1, 2009, 37 (8) 1738-1748; DOI: https://doi.org/10.1124/dmd.108.025981
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