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Research ArticleArticle

In Vitro Interactions between a Potential Muscle Relaxant E2101 and Human Cytochromes P450

Zhi-Yi Zhang, Belinda M. King, Nevena N. Mollova and Y. Nancy Wong
Drug Metabolism and Disposition July 2002, 30 (7) 805-813; DOI: https://doi.org/10.1124/dmd.30.7.805
Zhi-Yi Zhang
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Belinda M. King
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Nevena N. Mollova
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Y. Nancy Wong
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Abstract

E2101 orN-methyl-[1-[1-(2-fluorophenethyl)piperidine-4-yl]-1H-indol-6-yl] acetamide, an antagonist of 5-hydroxytryptamine receptor subtypes 1A and 2, is currently under development for the potential treatment of skeletal muscle associated spasticity. Here we characterized the in vitro metabolism of E2101 using human liver enzymes including human liver microsomal preparations, human liver S9 fractions, and individual forms of recombinant cytochromes P450 (P450s). Our results showed that E2101 was metabolized by P450s to form monohydroxylated (M1 and M2), dihydroxylated (M3), andN-dealkylated metabolites (M4). The structures of these major microsomal metabolites were proposed based on LC/MS/MS analyses. All four metabolites, M1–M4, were formed by CYP3A4. Metabolites, M1, M2, and M4, were also formed by CYP2C19 and M2 and M3 by CYP2D6. The potential P450 inhibition and induction of E2101 were also evaluated. E2101 was determined to be a competitive inhibitor of CYP2C19 and CYP2D6 with Ki of 15 and 48 μM, respectively, as determined by both Dixon plots and simultaneously nonlinear regression analyses. Induction of major P450 expression was not detected immunochemically after 72-h exposure to 10 or 50 μM E2101 in primary hepatocyte cultures obtained from three subjects. Taken together, E2101 is expected to metabolically interact with major human P450 enzymes including CYP2C19, CYP2D6, and CYP3A4, and a low risk of drug-drug interaction would be anticipated in clinical studies.

Footnotes

  • ↵1 Present address: Department of Pharmacokinetic and Pharmacodynamic Sciences, Genetics Institute, Andover, Massachusetts

  • Abbreviations used are::
    E2101
    N-methyl-[1-[1-(2-fluorophenethyl)piperidine-4-yl]-1H-indol-6-yl] acetamide
    5-HT
    5-hydroxytryptamine
    CNS
    central nervous system
    SSRI
    serotonin-selective reuptake inhibitor
    TRIZMA
    tris(hydroxymethyl)aminomethane
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    HPLC
    high-performance liquid chromatography
    LC/MS
    liquid chromatography/mass spectrometry
    MS/MS
    triple quadrupole mass spectrometer
    HLM
    human liver microsomal preparations
    IS
    internal standard
    SNLR
    simultaneously nonlinear regression analyses
    CID
    collision-induced dissociation
    PBS
    phosphate-buffered saline
    PDA
    photodiode array detector
    ESI
    electrospray ionization
    MRM
    multiple reaction monitoring
    HLS9
    human liver S9 fractions
    P450
    cytochrome P450
    GC
    gas chromatography
    • Received January 14, 2002.
    • Accepted March 21, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (7)
Drug Metabolism and Disposition
Vol. 30, Issue 7
1 Jul 2002
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Research ArticleArticle

In Vitro Interactions between a Potential Muscle Relaxant E2101 and Human Cytochromes P450

Zhi-Yi Zhang, Belinda M. King, Nevena N. Mollova and Y. Nancy Wong
Drug Metabolism and Disposition July 1, 2002, 30 (7) 805-813; DOI: https://doi.org/10.1124/dmd.30.7.805

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Research ArticleArticle

In Vitro Interactions between a Potential Muscle Relaxant E2101 and Human Cytochromes P450

Zhi-Yi Zhang, Belinda M. King, Nevena N. Mollova and Y. Nancy Wong
Drug Metabolism and Disposition July 1, 2002, 30 (7) 805-813; DOI: https://doi.org/10.1124/dmd.30.7.805
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