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Research ArticleArticle

Hydrastine Pharmacokinetics and Metabolism after a Single Oral Dose of Goldenseal (Hydrastis canadensis) to Humans

Prem K. Gupta, Gary Barone, Bill J. Gurley, E. Kim Fifer and Howard P. Hendrickson
Drug Metabolism and Disposition April 2015, 43 (4) 534-552; DOI: https://doi.org/10.1124/dmd.114.059410
Prem K. Gupta
Department of Pharmaceutical Sciences, College of Pharmacy (P.K.G., B.J.G., E.K.F., H.P.H.), and Department of Surgery, College of Medicine (G.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Gary Barone
Department of Pharmaceutical Sciences, College of Pharmacy (P.K.G., B.J.G., E.K.F., H.P.H.), and Department of Surgery, College of Medicine (G.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Bill J. Gurley
Department of Pharmaceutical Sciences, College of Pharmacy (P.K.G., B.J.G., E.K.F., H.P.H.), and Department of Surgery, College of Medicine (G.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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E. Kim Fifer
Department of Pharmaceutical Sciences, College of Pharmacy (P.K.G., B.J.G., E.K.F., H.P.H.), and Department of Surgery, College of Medicine (G.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Howard P. Hendrickson
Department of Pharmaceutical Sciences, College of Pharmacy (P.K.G., B.J.G., E.K.F., H.P.H.), and Department of Surgery, College of Medicine (G.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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  • Fig. 1.
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    Fig. 1.

    Analysis of chemical constituents of goldenseal supplement. (A) Mass spectrum of goldenseal extract diluted in methanol containing 0.1% formic acid. Diluted extract was directly infused into the electrospray source and mass analyzer at a flow rate of 10 µl/min. The inset shows the area of spectrum from m/z 325 to 400. Peaks (m/z) corresponding to berberine, canadine, berberastine, canadaline, and hydrastine are numbered 1, 2, 3, 4, and 5, respectively. (B) Extracted ion chromatograms (m/z 336, 340, 352, 370, and 384) from injection of diluted goldenseal extract. Ion chromatograms were chosen based on the expected m/z for berberine, canadine, berberastine, canadaline, and hydrastine.

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    Fig. 2.

    Serum concentration time profile for hydrastine following administration of 2.7 g of goldenseal extract (containing 78 mg hydrastine) to healthy human volunteers. Circles are the mean ± S.E.M. (n = 11). The solid line was generated using a noncompartmental technique based on the method of residuals.

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    Fig. 3.

    Characteristic fragmentation pathway used in structure assignment of hydrastine metabolites. The mass spectrum was extracted from the chromatographic peak for hydrastine. Ionization was achieved using an electrospray interface operated in the positive ion mode.

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    Fig. 4.

    Typical LC-Time of Flight Mass Spectrometric (ToFMS) chromatograms of urine following goldenseal consumption. (A–E) represent unique extracted ion chromatograms from the same injection of urine. Proposed structure assignments for each peak are shown in Table 2.

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    Fig. 5.

    Proposed phase I and II metabolism of hydrastine. Specific enzymes are provided when possible, and assignment of these enzymes was made based on known metabolic reactions for noscapine, a naturally occurring structural analog of hydrastine. CYP = cyctochrome P450; MAO = monoamine oxidase; PON1 = human serum paraoxonase.

Tables

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    TABLE 1

    Pharmacokinetic parameters for hydrastine

    Values are the mean ± standard deviation (n = 11).

    DosetmaxCmaxAUCt1/2Dose Excreted in Urine
    hng/mlng⋅h/mlh%
    1.13 ± 0.311.2 ± 0.3208 ± 126495 ± 2174.8 ± 1.40.16 ± 0.14
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    TABLE 2

    Exact mass and structure for diagnostic product ions observed in tandem mass spectrum analysis of hydrastine metabolites

    m/zMetabolites with This Product IonStructure of Product Ion
    206.0812M39Embedded Image
    192.1019M20, M21, M37, M40, M41Embedded Image
    190.0863Hydrastine, M11, M12, M15, M18, M19Embedded Image
    188.0706M10, M13, M14Embedded Image
    178.0863M16, M27, M29, M30, M32, M33,Embedded Image
    176.0706M25, M34Embedded Image
    • View popup
    TABLE 3

    Chromatographic and ESI-TOF data of hydrastine and proposed metabolites in urine from healthy volunteers following oral administration of 2.7 g of goldenseal supplement (equivalent to 78 mg of hydrastine)

    IdentifierProposed ReactiontRExpected IonMeasured IonFormulaPeak AreaaHydrastineMS/MS FragmentsProposed Structure
    minm/zm/z%m/z
    HydrastineParent37.3384.1447384.1430C21H20NO6625 ± 390100190.0892bEmbedded Image
    293.0850
    323.0825
    M1C-C reduction14.2192.1024192.1018 (+1.0)C11H13NO2261 ± 13534177.0787Embedded Image Hydrohydrastinin
    162.0776
    M2C-C reduction25.5195.0657195.0661 (2.0)C10H11O445 ± 196180.0443Embedded ImageMeconine
    162.0320
    M3C-C reduction, dehydrogenation/C-C reduction, C-O reduction, aromatization15.4, 15.8190.0868190.0866 (−1.0), 190.0879 (+5.7)C11H12NO21167 ± 509; 778 ± 312151M3: 175.0633Embedded Image
    147.0677
    154.0508
    132.0365
    M4101M4: 175.0626
    160.0755
    149.0581
    132.0365
    M5C-C reduction, aromatization15.6188.0712188.0714 (+1.0)C11H10NO23860 ± 1442500130.0555, 160.0676Embedded ImageHydrastonine
    M7C-C reduction, N-demethylation and N-sulfation11.9258.0436258.0434 (−0.8)C10H12NO6S137 ± 7218178.0868Embedded Image
    M9C-C reduction, N-demethylation, hydroxylation and O-glucuronidation22.4370.1138370.1138 (0)C16H20NO999 ± 7713194.0812Embedded Image
    M10C-C dehydrogenation30.8382.1291382.1278 (−3.4)C21H20NO674 ± 4210334.0744Embedded Image
    322.1118
    292.1011
    278.0926
    188.0712b
    M11Lactone hydrolysis, alcohol dehydrogenation27.6400.1396400.1388C21H22NO7 (−2.0)186 ± 5924382.1301Embedded Image
    190.0866b
    M12Hydroxylation37.3400.1396400.1402C21H22NO7 (+1.5)304 ± 15739190.0866bEmbedded Image
    311.0924
    323.0917
    335.0938
    353.1053
    M13,14Lactone hydrolysis, dehydrogenation, acyl glucuronidation27.2, 28.8576.1717576.1706 (−1.9), 576.1705 (−2.1)C27H30NO1372 ± 509M13:Embedded Image
    382.1235
    188.0721b
    M14: 382.1181
    188.0697b
    M15C-C dehydrogenation32.4382.1291382.1289 (−0.5)C21H20NO6154 ± 9820322.1089Embedded Image CAS: 858196-25-5
    307.1242
    292.0983
    278.0943
    280.1007
    190.0882b
    M16C-O reduction, O-demethylation21.4372.1447372.1437 (−2.7)C20H22NO6178 ± 10023354.1255Embedded Image CAS: 58298-46-7
    323.0909
    311.0941
    178.0859b
    M18O-demethylation, O-sulfation27.4450.0860450.0851 (−1.8)C20H20NO9S73 ± 709370.1304Embedded Image
    309.0805
    190.0887b
    M19O-demethylation, O-glucuronidation19.9546.1612546.1607 (−0.9)C26H28NO12508 ± 35966370.1288Embedded Image
    309.0797
    190.0874b
    M20C-O reduction, O-demethylation, O-glucuronidation12.1548.1768548.1740 (−5.1)C26H30NO12355 ± 21146372.1447Embedded Image
    368.1266
    311.0951
    294.1451
    192.1035b
    M21C-O reduction, O-demethylation, O-glucuronidation12.5548.1768548.1758 (−1.8)C26H30NO12533 ± 31669372.1425
    323.0960
    311.0886
    192.1035b
    165.0651
    144.0820
    M22C-O reduction, O-demethylation, O-sulfation18.8452.1016452.1016 (0)C20H22NO9S117 ± 8115372.1456Embedded Image
    323.0952
    311.0924
    192.1018b
    M25N-demethylation, O-demethylation, O-glucuronidation19.3532.1455532.1452 (−0.6)C25H26NO12220 ± 13829514.1329Embedded Image
    356.1135
    338.1030
    176.0707b
    M 27C-O reduction, N-demethylation, O-demethylation, O-sulfation16.9438.0860438.0851 (−1.8)C19H20NO9S145 ± 8819358.1266Embedded Image
    258.0418
    297.0751
    178.0871b
    M 29C-O reduction, N-demethylation, O-demethylation, O-sulfation18.6438.0860438.0867 (1.8)C19H20NO9S48 ± 266358.1269
    178.0868b
    M 30C-O reduction, N-demethylation, O-demethylation, O-glucuronidation12.7534.1612534.1601 (−2.1)C25H28NO1274 ± 7310516.1489Embedded Image
    358.1084
    340.1005
    178.0872b
    M 31N-demethylation, C-O reduction31.2372.1447372.1447 (0)C20H22NO6280 ± 12836354.1348Embedded Image
    178.0875b
    323.1196
    M 32N-demethylation, C-O reduction, O-glucuronidation16.7548.1768548.1755 (−2.4)C26H30NO12579 ± 489 240 ± 10875M32: 372.1442Embedded Image
    354.1183
    178.0866b
    M 3317.3548.1753 (−2.7)31M33: 372.1435
    354.1173
    178.0865b
    M34N-demethylation34.3370.1290370.1300C20H20NO6176.0796bEmbedded Image Norhydrastine
    321.1010
    352.1186
    M 36Lactone hydrolysis34.0402.1553402.1543 (−2.5)C21H24NO7329 ± 20928384.1447Embedded Image
    366.1384
    353.1024
    335.0919
    323.0924
    M 37Lactone hydrolysis, C-O reduction, O-glucuronidation15.9580.2030580.2019 (−1.9)C27H34NO13768 ± 504100562.1642Embedded Image
    404.1642
    386.1659
    368.1326
    192.1000b
    M 39Hydroxylation, O-glucuronidation27.7576.1717576.1705 (−2.1)C27H30NO13235 ± 12538400.1353Embedded Image
    206.0389b
    451.2171
    467.1917
    M 40C-O reduction25.8386.1604386.1605 (0.3)C21H24NO6482 ± 24662368.1318Embedded Image
    337.1096
    325.1057
    192.1013b
    M 41C-O reduction, O-glucuronidation18.4562.1925562.1921 (−0.4)C27H32NO122389 ± 1145309386.1584Embedded Image
    368.1327
    325.1041
    192.1028b
    • ↵a Peak area was the chromatographic peak area from the extracted ion chromatogram. The extracted ion chromatogram was obtained from the (M+H)+ trace ± 0.2 atomic mass unit (amu).

    • ↵b Diagnostic fragment ion. See Figure 3 for proposed fragmentation mechanism.

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    TABLE 4

    Predicted metabolites of canadaline detected in urine following consumption of goldenseal supplement

    IdentifierReactiontRExpected IonMeasured IonFormulaPeak AreaMS/MS FragmentsProposed Structure
    minm/zm/zm/z
    Canadaline41.6370.1654370.1656 (0.5)C21H23NO5470190.0868aEmbedded Image
    M43C-O reduction, O-demethylation35.1358.1654358.1651 (−0.8)C20H24NO5177 ± 79, 311340.1559Embedded Image
    192.1015
    M44C-O reduction, O-demethylation, O-glucuronidation18.9534.1975534.1969 (−1.1)C26H32NO1129 ± 24, 50358.1Embedded Image
    192.1a
    M45C-O reduction, O-demethylation, O-glucuronidation24.8534.1975534.1959 (−3.0)C26H32NO1118 ± 11, 31358.1Embedded Image
    354.1
    178.1
    M46, M47C-O reduction33.3 33.7372.1811372.1809 (−0.5)C21H26NO5106 ± 39, 186; 136 ± 68, 225192.1Embedded Image
    272.1
    354.1
    M48C-O reduction, O-glucuronidation24.5, 27.0548.2132548.2111 (−3.8)C27H34NO11128 ± 68, 225; 549 ± 285, 964372.1809Embedded Image
Embedded Image
    M49548.2117 (−2.7)368.1339
    192.1034
    M50C-O reduction, O-sulfation33.3452.1379452.1360 (−4.5)C21H26NO8S500 ± 268, 877372.1799Embedded Image
    354.1687
    272.0598
    192.1031
    • ↵a Diagnostic fragment ion. See Figure 3 for proposed fragmentation mechanism.

    • View popup
    TABLE 5

    Area under the chromatographic peak area versus time and elimination half-life curve for each serum metabolite

    Identifierm/zAUC (Peak Area × h)aTmaxt1/2Proposed Structure
    hh
    Hydrastine3866435 ± 30271.2 ± 0.34.8 ± 1.4Embedded Image
    M1 (hydrohydrastinin)1926966 ± 43811.4 ± 0.322 ± 18Embedded Image
    M364022745 ± 17591.2 ± 0.45 ± 2Embedded Image
    M415627797 ± 79243.0 ± 111 ± 15Embedded Image
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Drug Metabolism and Disposition: 43 (4)
Drug Metabolism and Disposition
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1 Apr 2015
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Research ArticleArticle

Hydrastine ADME in Humans after a Single Dose of Goldenseal

Prem K. Gupta, Gary Barone, Bill J. Gurley, E. Kim Fifer and Howard P. Hendrickson
Drug Metabolism and Disposition April 1, 2015, 43 (4) 534-552; DOI: https://doi.org/10.1124/dmd.114.059410

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Research ArticleArticle

Hydrastine ADME in Humans after a Single Dose of Goldenseal

Prem K. Gupta, Gary Barone, Bill J. Gurley, E. Kim Fifer and Howard P. Hendrickson
Drug Metabolism and Disposition April 1, 2015, 43 (4) 534-552; DOI: https://doi.org/10.1124/dmd.114.059410
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