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Research ArticleArticle

Metabolism, Pharmacokinetics, and Excretion of a Highly SelectiveN-Methyl-d-aspartate Receptor Antagonist, Traxoprodil, in Human Cytochrome P450 2D6 Extensive and Poor Metabolizers

Kim Johnson, Ajit Shah, Sarah Jaw-Tsai, James Baxter and Chandra Prakash
Drug Metabolism and Disposition January 2003, 31 (1) 76-87; DOI: https://doi.org/10.1124/dmd.31.1.76
Kim Johnson
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Ajit Shah
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Sarah Jaw-Tsai
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James Baxter
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Chandra Prakash
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Abstract

The excretion, biotransformation, and pharmacokinetics of a selective N-methyl-d-aspartate receptor antagonist, traxoprodil, were investigated in six healthy male volunteers, phenotyped either as CYP2D6 extensive or poor metabolizers of dextromethorphan. Each subject received an i.v. infusion of a single 50-mg (100 μCi) dose of [14C]traxoprodil. Approximately 89% of the administered dose was recovered in poor metabolizers (PMs) and 61% in extensive metabolizers (EMs), with the majority of the dose being excreted in the urine (86% in PMs and 52% in EMs). The elimination of traxoprodil was more rapid in EMs than in PMs with terminal elimination half-lives of 2.8 and 26.9 h, respectively, for EMs and PMs. Area under the plasma concentration-time curve from time 0 to T (AUC(0-Tlast)) values for unchanged traxoprodil were 1.2 and 32.7% of the corresponding AUC values for total radioactivity in EMs and PMs, respectively. Traxoprodil was metabolized in both EMs and PMs, with ∼7 and 50% of the administered radioactivity excreted as unchanged drug in the excreta of EMs and PMs, respectively. Hydroxylation at the 3-position of the hydroxyphenyl ring and methylation of the resulting catechol followed by conjugation were identified as the main metabolic pathways in EMs. In contrast, direct conjugation of traxoprodil with glucuronic or sulfuric acid was the major pathway in PMs. In vitro studies using CYP2D6-selective inhibitor and recombinant enzyme also support that the metabolism of traxoprodil is mainly mediated by CYP2D6. Taken together, these studies suggest that traxoprodil is eliminated mainly by Phase I oxidative metabolism mediated by CYP2D6 isozyme in EMs and by Phase II conjugation and renal clearance of parent in PMs.

Footnotes

  • Abbreviations used are::
    Traxoprodil
    CP-101,606, [(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol mesylate]
    NMDA
    N-methyl-d-aspartate
    EM
    extensive metabolizer
    PM
    poor metabolizer
    LC/MS/MS
    liquid chromatography-tandem mass spectrometry
    P450
    cytochrome P450
    HPLC
    high performance liquid chromatography
    LSC
    liquid scintillation counting
    Kel
    the terminal phase rate constant
    T1/2
    terminal phase half-life
    AUC0-T
    area under the plasma concentration-time curve from time 0 to T
    AUMC0-T
    area under the moment curve from time 0 to T
    CLp
    systemic plasma clearance
    MRT
    mean residence time
    VDss
    steady-state volume of distribution
    β-RAM
    radioactive monitor
    CAD
    collisionally activated dissociation
    amu
    atomic mass unit(s)
    MS
    mass spectrometry
    3-hydroxy-traxoprodil
    4-[1-hydroxy-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-propyl]-benzene-1,2-diol
    3-methoxy-traxoprodil
    1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol
    4′-hydroxy-traxoprodil
    1-[2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]-4-(4-hydroxy-phenyl)-piperidin-4-ol
    2-OMe-E2
    2-methoxy-17β-estradiol
    2-OH-E2-3ME
    2-hydroxy-17β-estradiol-3-methyl ether
    • Received May 21, 2002.
    • Accepted September 28, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (1)
Drug Metabolism and Disposition
Vol. 31, Issue 1
1 Jan 2003
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Research ArticleArticle

Metabolism, Pharmacokinetics, and Excretion of a Highly SelectiveN-Methyl-d-aspartate Receptor Antagonist, Traxoprodil, in Human Cytochrome P450 2D6 Extensive and Poor Metabolizers

Kim Johnson, Ajit Shah, Sarah Jaw-Tsai, James Baxter and Chandra Prakash
Drug Metabolism and Disposition January 1, 2003, 31 (1) 76-87; DOI: https://doi.org/10.1124/dmd.31.1.76

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Research ArticleArticle

Metabolism, Pharmacokinetics, and Excretion of a Highly SelectiveN-Methyl-d-aspartate Receptor Antagonist, Traxoprodil, in Human Cytochrome P450 2D6 Extensive and Poor Metabolizers

Kim Johnson, Ajit Shah, Sarah Jaw-Tsai, James Baxter and Chandra Prakash
Drug Metabolism and Disposition January 1, 2003, 31 (1) 76-87; DOI: https://doi.org/10.1124/dmd.31.1.76
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