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Research ArticleArticle

Pharmacokinetics of Oral d-Serine in d-Amino Acid Oxidase Knockout Mice

Rana Rais, Ajit G. Thomas, Krystyna Wozniak, Ying Wu, Hanna Jaaro-Peled, Akira Sawa, Christine A. Strick, Sandra J. Engle, Nicholas J. Brandon, Camilo Rojas, Barbara S. Slusher and Takashi Tsukamoto
Drug Metabolism and Disposition November 2012, 40 (11) 2067-2073; DOI: https://doi.org/10.1124/dmd.112.046482
Rana Rais
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Ajit G. Thomas
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Krystyna Wozniak
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Ying Wu
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Hanna Jaaro-Peled
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Akira Sawa
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Christine A. Strick
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Sandra J. Engle
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Nicholas J. Brandon
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Camilo Rojas
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Barbara S. Slusher
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Takashi Tsukamoto
Department of Neurology (R.R., B.S.S., T.T.), Brain Science Institute (A.G.T., K.W., Y.W., C.R.), and Department of Psychiatry and Behavioral Sciences (H.J.-P., A.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland; and Departments of Neuroscience (C.A.S., N.J.B.) and Pharmacokinetics, Dynamics and Metabolism (S.J.E.), Pfizer, Groton, Connecticut
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Abstract

d-Amino acid oxidase (DAAO) catalyzes the oxidative deamination of d-amino acids including d-serine, a full agonist at the glycine modulatory site of the N-methyl-d-aspartate (NMDA) receptor. To evaluate the significance of DAAO-mediated metabolism in the pharmacokinetics of oral d-serine, plasma d-serine levels were measured in both wild-type mice and transgenic mice lacking DAAO. Although d-serine levels were rapidly diminished in wild-type mice (t½ = 1.2 h), sustained drug levels over the course of 4 h (t½ > 10 h) were observed in mice lacking DAAO. Coadministration of d-serine with 6-chlorobenzo[d]isoxazol-3-ol (CBIO), a small-molecule DAAO inhibitor, in wild-type mice resulted in the enhancement of plasma d-serine levels, although CBIO seems to have only temporary effects on the plasma d-serine levels due to glucuronidation of the key hydroxyl group. These findings highlight the predominant role of DAAO in the clearance of d-serine from the systemic circulation. Thus, a potent DAAO inhibitor with a longer half-life should be capable of maintaining high plasma d-serine levels over a sustained period of time and might have therapeutic implications for the treatment of schizophrenia.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Mental Health [Grant R01-MH091387] (to T.T.); and the Johns Hopkins Brain Science Institute NeuroTranslational Drug Discovery program.

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

    http://dx.doi.org/10.1124/dmd.112.046482.

  • ABBREVIATIONS:

    NMDA
    N-methyl-d-aspartate
    DAAO
    d-amino acid oxidase
    CBIO
    6-chlorobenzo[d]isoxazol-3-ol
    OPA
    o-phthaldialdehyde
    HPLC
    high-performance liquid chromatography
    Boc-l-Cys
    N-tert-butyloxycarbonyl-l-cysteine
    KO
    knockout
    AA
    amino acid
    Cmax
    maximum plasma concentration
    Tmax
    time to Cmax
    AUC
    area under the plasma concentration time curve
    UDPGA
    uridine 5′-diphospho-glucuronic acid
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    IS
    internal standard
    MK801
    (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
    BAC
    bacterial artificial chromosome
    PCR
    polymerase chain reaction.

  • Received April 30, 2012.
  • Accepted July 26, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (11)
Drug Metabolism and Disposition
Vol. 40, Issue 11
1 Nov 2012
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Research ArticleArticle

ORAL d-SERINE PK IN MICE LACKING DAAO

Rana Rais, Ajit G. Thomas, Krystyna Wozniak, Ying Wu, Hanna Jaaro-Peled, Akira Sawa, Christine A. Strick, Sandra J. Engle, Nicholas J. Brandon, Camilo Rojas, Barbara S. Slusher and Takashi Tsukamoto
Drug Metabolism and Disposition November 1, 2012, 40 (11) 2067-2073; DOI: https://doi.org/10.1124/dmd.112.046482

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Research ArticleArticle

ORAL d-SERINE PK IN MICE LACKING DAAO

Rana Rais, Ajit G. Thomas, Krystyna Wozniak, Ying Wu, Hanna Jaaro-Peled, Akira Sawa, Christine A. Strick, Sandra J. Engle, Nicholas J. Brandon, Camilo Rojas, Barbara S. Slusher and Takashi Tsukamoto
Drug Metabolism and Disposition November 1, 2012, 40 (11) 2067-2073; DOI: https://doi.org/10.1124/dmd.112.046482
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