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Research ArticleArticle

In Vitro and In Vivo Metabolism and Pharmacokinetics of BMS-562086, a Potent and Orally Bioavailable Corticotropin-Releasing Factor-1 Receptor Antagonist

Lian Zhou, Randy C. Dockens, Peggy Liu-Kreyche, Scott J. Grossman and Ramaswamy A. Iyer
Drug Metabolism and Disposition June 2012, 40 (6) 1093-1103; DOI: https://doi.org/10.1124/dmd.111.043596
Lian Zhou
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Randy C. Dockens
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Peggy Liu-Kreyche
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Scott J. Grossman
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Ramaswamy A. Iyer
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Abstract

The absorption, distribution, metabolism, and excretion (ADME) and the pharmacokinetic characteristics of BMS-562086 [pexacerfont; 8-(6-methoxy-2-methyl-3-pyridinyl)-2,7-dimethyl-N-[(1R)-1-methylpropyl]pyrazolo(1,5-a)-1,3,5-triazin-4-amine (DPC-A69448)] were investigated in vitro and in animals to support its clinical development. BMS-562086 was orally bioavailable in rats, dogs, and chimpanzees, with an absolute oral bioavailability of 40.1, 58.8, and 58.5%, respectively. BMS-562086 was extensively metabolized in hepatocytes from all species and completely metabolized in rats. The primary biotransformation pathways found for BMS-562086 in both liver microsomal and hepatocyte preparations and in rats were similar. These included O-demethylation, hydroxylation at the N-alkyl side chain and N-dealkylation. Multiple cytochromes P450 including CYP3A4/5 were involved in the metabolic clearance of BMS-562086. Both renal and biliary excretion played a significant role in elimination of the metabolites of BMS-562086. The involvement of other metabolic enzymes in addition to CYP3A4/5 in elimination of BMS-562086 suggests a reduced potential for drug-drug interaction through modulation of CYP3A4/5. Chimpanzees proved to be a good animal model in predicting BMS-562086 human clearance. Virtual clinical trials performed with a population-based ADME simulator suggested that a minimal dose of 100 mg daily would provide sufficient drug exposure to achieve plasma concentrations above the projected human efficacious plasma concentration of BMS-562086 (>500 nM). In summary, BMS-562086 exhibited favorable ADME and pharmacokinetic properties for further development.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.043596.

  • ABBREVIATIONS:

    CRF
    corticotropin-releasing factor
    IBS
    irritable bowel syndrome
    BMS-562086
    8-(6-methoxy-2-methyl-3-pyridinyl)-2,7-dimethyl-N-[(1R)-1-methylpropyl]pyrazolo(1,5-a)-1,3,5-triazin-4-amine
    ADME
    absorption, distribution, metabolism, and excretion
    BDC
    bile duct-cannulated
    DPH-123554
    O-demethylated metabolite of BMS-562086
    DPH-124921
    N-dealkylated metabolite of BMS-562086
    BMS-572273
    N-dealkylated and hydrolyzed metabolite of BMS-562086
    AP
    apical
    BL
    basolateral
    TEER
    transepithelial electrical resistance
    7-EC
    7-ethoxycoumarin
    7-HC
    7-hydroxycoumarin
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    QC
    quality control
    Cmax
    maximal observed concentration
    Tmax
    time of maximal observed concentration
    AUC(INF)
    area under the plasma concentration-time curve from time zero extrapolated to infinite time
    CLb
    blood clearance
    CLp
    plasma clearance
    dQ/dt
    appearance rate
    VZ
    terminal volume of distribution
    F
    oral bioavailability.

  • Received October 29, 2011.
  • Accepted March 1, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (6)
Drug Metabolism and Disposition
Vol. 40, Issue 6
1 Jun 2012
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Research ArticleArticle

METABOLISM AND PHARMACOKINETICS OF BMS-562086

Lian Zhou, Randy C. Dockens, Peggy Liu-Kreyche, Scott J. Grossman and Ramaswamy A. Iyer
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1093-1103; DOI: https://doi.org/10.1124/dmd.111.043596

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Research ArticleArticle

METABOLISM AND PHARMACOKINETICS OF BMS-562086

Lian Zhou, Randy C. Dockens, Peggy Liu-Kreyche, Scott J. Grossman and Ramaswamy A. Iyer
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1093-1103; DOI: https://doi.org/10.1124/dmd.111.043596
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