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Research ArticleArticle

Metabolism and Excretion of Asenapine in Healthy Male Subjects

S. F. M. van de Wetering-Krebbers, P. L. Jacobs, G. J. Kemperman, E. Spaans, P. A. M. Peeters, L. P. C. Delbressine and M. L. P. S. van Iersel
Drug Metabolism and Disposition April 2011, 39 (4) 580-590; DOI: https://doi.org/10.1124/dmd.110.036715
S. F. M. van de Wetering-Krebbers
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P. L. Jacobs
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G. J. Kemperman
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E. Spaans
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P. A. M. Peeters
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L. P. C. Delbressine
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M. L. P. S. van Iersel
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The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of [14C]-asenapine to healthy male volunteers. Mean total excretion on the basis of the percent recovery of the total radioactive dose was ∼90%, with ∼50% appearing in urine and ∼40% excreted in feces; asenapine itself was detected only in feces. Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N+-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N+-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.

Footnotes

  • This work was supported by Schering-Plough Corporation; and Pfizer Inc. Editorial support was provided by Complete Healthcare Communications, Inc., and funded by Merck.

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

    doi:10.1124/dmd.110.036715.

  • ABBREVIATIONS:

    LSC
    liquid scintillation counting
    HPLC
    high-performance liquid chromatography
    SPE
    solid-phase extraction
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    MS
    mass spectrometry
    ES
    electrospray
    a.o.
    among others
    MIM
    monoisotopic molecular mass
    TOCSY
    total correlation spectroscopy
    2D
    two-dimensional
    SK&F 86466
    6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine.

  • Received October 12, 2010.
  • Accepted December 22, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (4)
Drug Metabolism and Disposition
Vol. 39, Issue 4
1 Apr 2011
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Research ArticleArticle

Metabolism and Excretion of Asenapine in Healthy Male Subjects

S. F. M. van de Wetering-Krebbers, P. L. Jacobs, G. J. Kemperman, E. Spaans, P. A. M. Peeters, L. P. C. Delbressine and M. L. P. S. van Iersel
Drug Metabolism and Disposition April 1, 2011, 39 (4) 580-590; DOI: https://doi.org/10.1124/dmd.110.036715

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Research ArticleArticle

Metabolism and Excretion of Asenapine in Healthy Male Subjects

S. F. M. van de Wetering-Krebbers, P. L. Jacobs, G. J. Kemperman, E. Spaans, P. A. M. Peeters, L. P. C. Delbressine and M. L. P. S. van Iersel
Drug Metabolism and Disposition April 1, 2011, 39 (4) 580-590; DOI: https://doi.org/10.1124/dmd.110.036715
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