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Research ArticleArticle

Metabolism and Disposition of Hepatitis C Polymerase Inhibitor Dasabuvir in Humans

Jianwei Shen, Michael Serby, Aimee Reed, Anthony J. Lee, Rajeev Menon, Xiaomei Zhang, Kennan Marsh, Xia Wan, Olga Kavetskaia and Volker Fischer
Drug Metabolism and Disposition August 2016, 44 (8) 1139-1147; DOI: https://doi.org/10.1124/dmd.115.067512
Jianwei Shen
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Michael Serby
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Aimee Reed
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Anthony J. Lee
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Rajeev Menon
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Xiaomei Zhang
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Kennan Marsh
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Xia Wan
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Olga Kavetskaia
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Volker Fischer
Drug Metabolism and Pharmacokinetics, Research & Development (J.S., M.S., A.J.L., X.Z., V.F.), Process Chemistry (A.R.), Clinical Pharmacology and Pharmacometrics–Clinical Pharmacokinetics/Pharmacodynamics (R.M.), Exploratory Science (K.M.), and Drug Analysis (X.W., O.K.), AbbVie, North Chicago, Illinois
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Figures

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  • Fig. 1.
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    Fig. 1.

    Structure of [14C]dasabuvir and synthetic metabolites.

  • Fig. 2.
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    Fig. 2.

    Mean cumulative percent of radioactive dose recovered in urine and feces at specified intervals after a single 400-mg (100 µCi) oral dose of [14C]dasabuvir to healthy male subjects.

  • Fig. 3.
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    Fig. 3.

    Mean (S.D.) plasma concentration-time curves for dasabuvir (in nanograms per milliliter) and total radioactivity (in nanogram equivalents per gram) in male subjects administered a single 400-mg oral dose of [14C]dasabuvir (N = 4).

  • Fig. 4.
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    Fig. 4.

    Representative HPLC radiochromatograms of dasabuvir and its metabolites in human plasma after a single 400-mg oral dose of [14C]dasabuvir. CPM, counts per minute.

  • Fig. 5.
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    Fig. 5.

    Representative HPLC radiochromatograms of dasabuvir and its metabolites in human excreta, urine (A) and feces (B), after a single 400-mg oral dose of [14C]dasabuvir. CPM, counts per minute; RT, retention time.

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    Fig. 6.

    Proposed metabolic pathways of dasabuvir in humans.

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    Fig. 7.

    Representative HPLC radiochromatograms of dasabuvir and its metabolites in recombinant human CYP2C8 (A), CYP3A4 (B), CYP2D6 (C) and CYP2B6 (D) isoforms.

Tables

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    TABLE 1

    Pharmacokinetic parameters of total radioactivity, dasabuvir, and metabolite M1

    Data are presented as means ± S.D.

    AnalyteCmaxTmaxAUC0–lastAUC0–∞t1/2
    ngEq/g or ng/mlhngEq/g or ng/mlh
    Total radioactivity1300 ± 5864 ± 08251 ± 31119959 ± 3414
    Dasabuvir658 ± 2524 ± 06260 ± 19306290 ± 19308.4 ± 3.2
    M1267 ± 1163.0 ± 1.22230 ± 9482280 ± 9346.2 ± 1.3
    • t1/2, half-life.

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    TABLE 2

    Percentages of radioactivity for dasabuvir and corresponding metabolites in human plasma (N = 4) after administration of a single 400-mg oral dose of [14C]dasabuvir

    Data are presented as means ± S.D.

    MetabolitePercentage of Radioactivity in Plasma
    Dasabuvir58.1 ± 4.6
    M121.4 ± 2.4
    M26.6 ± 2.4
    M34.4 ± 3.0
    M41.7 ± 1.3
    M51.7 ± 1.7
    M62.3 ± 2.0
    U14.7 ± 1.1
    • View popup
    TABLE 3

    Percentages of excretory metabolites of dasabuvir in humans (N = 4) after administration of a single 400-mg oral dose of [14C]dasabuvir

    MetaboliteFecesUrineTotal
    0–216 h0–24 h
    Total radioactivity94.42.20a96.6
    Dasabuvir26.20.0326.2
    M131.50.8532.4
    M215.20.315.5
    M3ND0.190.19
    M4ND0.120.12
    M511.10.1211.2
    M6ND0.020.02
    M7ND0.380.38
    M82.05ND2.05
    M94.91ND4.91
    M103.37ND3.37
    M11ND0.030.03
    U1ND0.010.01
    • ND, not determined.

    • ↵a Total radioactivity for urine is 0–216 hours.

    • View popup
    TABLE 4

    Retention time, molecular ions, and characteristic fragment ions of dasabuvir and metabolites in human plasma, urine, or feces

    CompoundObserved
[M-H]−Theoretical
[M-H]−Mass ErrorMetabolite IDCharacteristicFragment Ionsb
    ppm
    Dasabuvir492.1601492.15990.41Parent drug477c (−CH3), 462 (−2 CH3), 449 (−NCO), 435 (−C4H9), 414 (−SO2CH2), 399 (−SO2CH2 and −CH3)
    M1508.1550508.15480.39P +O493c (−CH3), 476 (−CH3OH), 463 (−C2H5O), 435 (−C4H9O), 430 (−SO2CH2), 415 (−SO2CH2 and −CH3), 399 (−SO2CH2 and −CH3O)
    M2588.1111588.1116−0.85M1 sulfate545 (−NCO), 509c (−CH3SO2), 494 (−CH3SO2 and −CH3), 466 (−NCO and −CH3SO2), 465 (−NCO and −SO3), 433 (−NCO and −CH4SO4)
    M3684.1861684.1869−1.17M1 glucuronide641 (−NCO), 597 (−NCO and −CO2), 476c (−C7H12O7), 433 (−C7H12O7 and −NCO)
    M4506.1381506.1391−1.98M1 −2H463c (−C2H3O), 435 (−C4H7O), 413 (−SO2CH2 and −CH3)
    M5522.1337522.1340−0.57P +2O, −2H507 (−CH3), 478 (−CO2), 463c (−C2H3O2), 435 (−C4H7O2)
    M6698.1657698.1661−0.57M5 glucuronide522 (−C6H8O6), 478c (−C6H8O6 and −CO2), 463(−C6H8O6, −CO2, and −CH3), 383 (−C6H8O6, −CO2, −CH3, −CH4SO2)
    M7700.1801700.1818−2.43M6 +2H524c (−C6H8O6), 444 (−C6H8O6 and −CH4SO2)
    M8a524.1487524.1497−1.91M5 +2H480 (−CO2), 465c (−C2H3O2), 437 (−C4H7O2), 401 (−CO2 and −CH3SO2), 387 (−CO2, −CH2SO2, and −CH3)
    M9a510.1694510.1704−1.96M1 +2H495c (−CH3), 478 (−CH3OH), 465 (−C2H5O), 452, 437 (−C4H9O)
    M10a590.1260590.1272−2.03M2 +2HN/A
    M11494.1380494.1391−2.33M1 –CH2479c (−CH3), 464 (−2 CH3), 416 (−SO2CH2), 401 (−SO2CH2 and −CH3)
    • N/A, not available; P, parent drug.

    • ↵a Observed only in fecal samples.

    • ↵b Minus signs indicate loss.

    • ↵c base fragment ion.

Additional Files

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  • Data Supplement

    Files in this Data Supplement:

    • Supplemental Data -

      Additional MS/MS Spectra of metabolites

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Drug Metabolism and Disposition: 44 (8)
Drug Metabolism and Disposition
Vol. 44, Issue 8
1 Aug 2016
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Research ArticleArticle

Metabolism and Disposition of [14C]Dasabuvir in Humans

Jianwei Shen, Michael Serby, Aimee Reed, Anthony J. Lee, Rajeev Menon, Xiaomei Zhang, Kennan Marsh, Xia Wan, Olga Kavetskaia and Volker Fischer
Drug Metabolism and Disposition August 1, 2016, 44 (8) 1139-1147; DOI: https://doi.org/10.1124/dmd.115.067512

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Research ArticleArticle

Metabolism and Disposition of [14C]Dasabuvir in Humans

Jianwei Shen, Michael Serby, Aimee Reed, Anthony J. Lee, Rajeev Menon, Xiaomei Zhang, Kennan Marsh, Xia Wan, Olga Kavetskaia and Volker Fischer
Drug Metabolism and Disposition August 1, 2016, 44 (8) 1139-1147; DOI: https://doi.org/10.1124/dmd.115.067512
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