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Research ArticleArticle

Metabolism of Vabicaserin in Mice, Rats, Dogs, Monkeys, and Humans

Zeen Tong, Appavu Chandrasekaran, William DeMaio, Robert Espina, Wei Lu, Ronald Jordan and JoAnn Scatina
Drug Metabolism and Disposition December 2010, 38 (12) 2266-2277; DOI: https://doi.org/10.1124/dmd.110.033670
Zeen Tong
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Appavu Chandrasekaran
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William DeMaio
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Robert Espina
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Wei Lu
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Ronald Jordan
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JoAnn Scatina
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Abstract

Vabicaserin is a potent 5-hydroxytryptamine2C agonist that is currently being developed for the treatment of the psychotic symptoms of schizophrenia. In this study, in vitro and in vivo metabolism of vabicaserin was evaluated in mice, rats, dogs, monkeys, and humans, and the structures of the metabolites were characterized by liquid chromatography/mass spectrometry and NMR spectroscopy. Vabicaserin underwent three major metabolic pathways in vitro: NADPH-dependent hydroxylation, NADPH-independent imine formation, and carbamoyl glucuronidation. After a single oral dose, vabicaserin was extensively metabolized in animals and humans, and its metabolites were mainly excreted via the urine in mice and rats. Along with the metabolites observed in vitro, secondary metabolism via oxidation and conjugation of the primary metabolites generated from the above-mentioned three pathways yielded a number of additional metabolites in vivo. Carbamoyl glucuronidation was the major metabolic pathway in humans but a minor pathway in rats. Although carbamoyl glucuronidation was a major metabolic pathway in mice, dogs, and monkeys, oxidative metabolism was also extensive in these species. Hydroxylation occurred in all species, although different regional selectivity was apparent. The imine pathway also appeared to be common to several species, because vabicaserin imine was observed in humans and hydroxyl imine metabolites were observed in mice, rats, and dogs. A nitrone metabolite of vabicaserin was observed in dogs and humans but not in other species. In conclusion, the major metabolic pathways for vabicaserin in humans and nonclinical safety species include carbamoyl glucuronidation, hydroxylation, formation of an imine, and a nitrone.

Footnotes

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

    doi:10.1124/dmd.110.033670.

  • ABBREVIATIONS:

    5-HT
    5-hydroxytryptamine
    CG
    carbamoyl glucuronide
    UDPGA
    uridine 5′-diphosphoglucuronic acid trisodium salt
    LC/MS
    liquid chromatography/mass spectrometry
    mCPBA
    3-chloroperoxybenzoic acid
    HPLC
    high-performance liquid chromatography
    DMSO
    dimethyl sulfoxide
    LSC
    liquid scintillation counter
    HSQC
    heteronuclear single quantum correlation
    HMBC
    heteronuclear multiple-bond correlation
    2D
    two-dimensional
    WAY-280107
    1-O-[(9aR,12aS)-6,7,9,9a,1011,12,12a-octahydrocyclopenta[c][1,4]diazepino[6,7,1-ij]quinolin-5(4H)-ylcarbonyl]-d-glucopyranuronic acid.

  • Received March 31, 2010.
  • Accepted August 25, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (12)
Drug Metabolism and Disposition
Vol. 38, Issue 12
1 Dec 2010
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Research ArticleArticle

Metabolism of Vabicaserin in Mice, Rats, Dogs, Monkeys, and Humans

Zeen Tong, Appavu Chandrasekaran, William DeMaio, Robert Espina, Wei Lu, Ronald Jordan and JoAnn Scatina
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2266-2277; DOI: https://doi.org/10.1124/dmd.110.033670

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Research ArticleArticle

Metabolism of Vabicaserin in Mice, Rats, Dogs, Monkeys, and Humans

Zeen Tong, Appavu Chandrasekaran, William DeMaio, Robert Espina, Wei Lu, Ronald Jordan and JoAnn Scatina
Drug Metabolism and Disposition December 1, 2010, 38 (12) 2266-2277; DOI: https://doi.org/10.1124/dmd.110.033670
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