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Research ArticleArticle

In Vitro-In Vivo Correlation and Translation to the Clinical Outcome for CJ-13,610, a Novel Inhibitor of 5-Lipoxygenase

J. Matthew Hutzler, Collette D. Linder, Roger J. Melton, John Vincent and J. Scott Daniels
Drug Metabolism and Disposition July 2010, 38 (7) 1113-1121; DOI: https://doi.org/10.1124/dmd.110.032706
J. Matthew Hutzler
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Collette D. Linder
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Roger J. Melton
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John Vincent
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J. Scott Daniels
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Abstract

The metabolism of the 5-lipoxygenase inhibitor, 4-(3-(4-(2-methyl-1H-imidazol-1-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide (CJ-13,610), was investigated in liver microsomes from human and preclinical species in an effort to compare metabolite profiles and evaluate the in vitro-in vivo correlation for metabolic clearance. Overall, the metabolite profile of CJ-13,610 was comparable across the species tested with multiple oxidative metabolites observed, including sulfoxidation. The sulfoxidation kinetics characterized in rat, dog, and human liver microsomes (HLM) indicated a low apparent Michaelis-Menten constant (Km, app) of 4 to 5 μM. Results from cDNA-expressed cytochrome P450 (P450) studies indicated that the metabolism in HLM was primarily mediated by CYP3A4 and 3A5. A subsequent in vitro study using ketoconazole as an inhibitor of CJ-13,610 sulfoxidation corroborated the CYP3A4/5-mediated pathway (IC50 = 7 nM). Assessment of multiple methods for predicting the human pharmacokinetic profile observed with CJ-13,610 after a 30-mg single oral dose indicated that clearance scaled from human liver microsomes yielded a better prediction when coupled with a Vdss term that was scaled from dog [area under the concentration-time curve (AUC) and half-life within 1.3-fold of actual] versus a Vdss term obtained from rat. Single-species allometric scaling of clearance and Vdss from dog pharmacokinetic studies was equally predictive, whereas scaling from rat resulted in underpredictions of both AUC and maximal concentration (Cmax). Results from these studies support the strategy of predicting human pharmacokinetics using human liver microsomal intrinsic clearance data. More importantly, results from the present investigation enabled the selection of alternative drug candidates from the chemical series via in vitro screening, while subsequently eliminating costly routine preclinical in vivo studies.

Footnotes

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

    doi:10.1124/dmd.110.032706.

  • ABBREVIATIONS:

    CJ 13,610
    4-(3-(4-(2-methyl-1H-imidazol-1-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide
    5-LOX
    5-lipoxygenase
    LT
    leukotriene
    P450
    cytochrome P450
    CP-680179
    4-(3-(4-(2-methyl-1H-imidazol-1-yl)phenylsulfinyl)phenyl)-tetrahydro-2H-pyran-4-carboxamide
    LC
    liquid chromatography
    MS/MS
    mass spectrometry
    FMO
    flavin monooxygenase
    HPLC
    high-performance liquid chromatography
    AUC
    area under the concentration-time curve
    MRT
    mean residence time
    hFMO
    human flavin monooxygenase
    HLM
    human liver microsome(s)
    SSS
    single-species allometric scaling
    CLh
    hepatic clearance.

  • Received February 10, 2010.
  • Accepted April 7, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

In Vitro-In Vivo Correlation and Translation to the Clinical Outcome for CJ-13,610, a Novel Inhibitor of 5-Lipoxygenase

J. Matthew Hutzler, Collette D. Linder, Roger J. Melton, John Vincent and J. Scott Daniels
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1113-1121; DOI: https://doi.org/10.1124/dmd.110.032706

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Research ArticleArticle

In Vitro-In Vivo Correlation and Translation to the Clinical Outcome for CJ-13,610, a Novel Inhibitor of 5-Lipoxygenase

J. Matthew Hutzler, Collette D. Linder, Roger J. Melton, John Vincent and J. Scott Daniels
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1113-1121; DOI: https://doi.org/10.1124/dmd.110.032706
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