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Research ArticleArticle

Roles of UGT, P450, and Gut Microbiota in the Metabolism of Epacadostat in Humans

Jason Boer, Ruth Young-Sciame, Fiona Lee, Kevin J. Bowman, Xiaoqing Yang, Jack G. Shi, Frank M. Nedza, William Frietze, Laurine Galya, Andrew P. Combs, Swamy Yeleswaram and Sharon Diamond
Drug Metabolism and Disposition October 2016, 44 (10) 1668-1674; DOI: https://doi.org/10.1124/dmd.116.070680
Jason Boer
Incyte Corporation, Wilmington, Delaware
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Ruth Young-Sciame
Incyte Corporation, Wilmington, Delaware
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Fiona Lee
Incyte Corporation, Wilmington, Delaware
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Kevin J. Bowman
Incyte Corporation, Wilmington, Delaware
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Xiaoqing Yang
Incyte Corporation, Wilmington, Delaware
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Jack G. Shi
Incyte Corporation, Wilmington, Delaware
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Frank M. Nedza
Incyte Corporation, Wilmington, Delaware
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William Frietze
Incyte Corporation, Wilmington, Delaware
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Laurine Galya
Incyte Corporation, Wilmington, Delaware
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Andrew P. Combs
Incyte Corporation, Wilmington, Delaware
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Swamy Yeleswaram
Incyte Corporation, Wilmington, Delaware
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Sharon Diamond
Incyte Corporation, Wilmington, Delaware
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  • Fig. 1.
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    Fig. 1.

    In vitro consumption of EPA (5 μM) by individual recombinant human UGTs (0.5 mg/ml) over 1 hour.

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    Fig. 2.

    Formation of M11 from EPA (10 μM) and benzamidine from benzamidoxime (10 μM) by human liver mitochondria, microsomes, homogenate, S9 fraction and cytosol (2 mg/ml protein) over 30 minutes. Incubations were conducted in potassium phosphate buffer (pH 6.0) with NADH (2 mM).

  • Fig. 3.
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    Fig. 3.

    Representative extracted ion chromatograms showing ex vivo formation of M11 from EPA in human feces homogenate (a) and decrease in M11 formation from EPA in human feces homogenate by commonly prescribed antibiotics (b).

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    Fig. 4.

    Formation of M12 from M11 (10 μM) by human tissue microsomes (2 mg/ml protein) and S9 fractions (3 mg/ml protein) and recombinant cytochrome P450s (0.3 nmol/ml).

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    Fig. 5.

    Proposed major metabolic pathways of EPA in humans.

Tables

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    TABLE 1 

    Area under the curve (AUC0–12h) ratios of major EPA metabolites relative to EPA in humans following a single oral dose and at steady state.

    DoseDayEPAM9M11M12
    50 mg BID118.2NCNC
    1018.10.30.8
    • NC, Not calculable because most plasma concentrations were below the lower limit of quantitation.

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    TABLE 2 

    In vivo formation of M11 and M12 in mice given EPA with and without antibiotic or ABT pretreatment.

    Dose GroupAUC0-6h Ratio Relative to EPA
    EPAM11M12
    Control1.0000.2600.107
    Ciprofloxacin pretreatment1.0000.1190.044
    ABT pretreatment1.0000.3720.017
    AUC0-6h ratio relative to M11
     Control1.0000.411
     Ciprofloxacin pretreatment1.0000.372
     ABT pretreatment1.0000.045
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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
Vol. 44, Issue 10
1 Oct 2016
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Research ArticleArticle

Metabolism of Epacadostat in Humans

Jason Boer, Ruth Young-Sciame, Fiona Lee, Kevin J. Bowman, Xiaoqing Yang, Jack G. Shi, Frank M. Nedza, William Frietze, Laurine Galya, Andrew P. Combs, Swamy Yeleswaram and Sharon Diamond
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1668-1674; DOI: https://doi.org/10.1124/dmd.116.070680

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Research ArticleArticle

Metabolism of Epacadostat in Humans

Jason Boer, Ruth Young-Sciame, Fiona Lee, Kevin J. Bowman, Xiaoqing Yang, Jack G. Shi, Frank M. Nedza, William Frietze, Laurine Galya, Andrew P. Combs, Swamy Yeleswaram and Sharon Diamond
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1668-1674; DOI: https://doi.org/10.1124/dmd.116.070680
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