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Prediction of Clinically Relevant Herb-Drug Clearance Interactions Using Sandwich-Cultured Human Hepatocytes: Schisandra spp. Case Study

Jonathan P. Jackson, Kimberly M. Freeman, Weslyn W. Friley, Ashley G. Herman, Christopher B. Black, Kenneth R. Brouwer and Amy L. Roe
Drug Metabolism and Disposition September 2017, 45 (9) 1019-1026; DOI: https://doi.org/10.1124/dmd.117.075408
Jonathan P. Jackson
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.)
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Kimberly M. Freeman
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.)
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Weslyn W. Friley
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.)
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Ashley G. Herman
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.)
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Christopher B. Black
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.)
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Kenneth R. Brouwer
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.)
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Amy L. Roe
Qualyst Transporter Solutions, Durham, North Carolina (J.P.J., K.M.F., W.W.F., A.G.H., C.B.B., and K.R.B.) and Procter & Gamble, Cincinnati, Ohio (A.L.R.)
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    Fig. 1.

    ATP content evaluation in SCHH following 24- (A) and 72-hour exposure to varying concentrations of SSE and SCE. Aflatoxin (10 µM) was used as a positive control cytotoxic agent. *P value ≤0.05 when compared with solvent control. Data are from a single experiment with treatments performed in triplicate wells. Mean values are reported ± S.D.

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    Fig. 2.

    Inhibition of CYP3A4/5 by SSE (A) or SCE (B), without preincubation (●) and with preincubation (■), evaluated in SCHH by monitoring the formation of OHMDZ from DZ. SSE no preincubation IC50 = 1.23 µg/ml, 95% confidence interval = 0.823–1.85, goodness of fit = 0.989; SSE preincubation IC50 = 0.378 µg/ml, 95% confidence interval = 0.299–0.479, goodness of fit = 0.999. SCE no preincubation IC50 = 4.46 µg/ml, 95% confidence interval = 4.44–4.48, goodness of fit = 1.0; SCE preincubation IC50 = 1.45 µg/ml, 95% confidence interval = 1.44–1.46, goodness of fit = 1.0. Data are from a single experiment with treatments performed in triplicate wells. Mean values are reported ± S.D.

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    Fig. 3.

    Relative-fold change of CYP3A4 mRNA content in SCHH following 72 hours of treatment with RIF (10 µM), SJW (20 µg/ml), SSE, or SCE. Error bars represent 95% confidence intervals. Data are from a single experiment with treatments performed in triplicate wells.

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    Fig. 4.

    Intracellular concentrations of schizandrin, gomisin A, and schisandrin A in SCHH following 72 hours of treatment with SSE or SCE. Data from a single experiment with treatments performed in triplicate wells. Mean values reported ± S.D.

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    Fig. 5.

    SCHH were treated with RIF, SJW, SSE, or SCE for 72 hours prior to an MDZ (1 µM) incubation of 24 hours, monitoring for depletion of substrate. Disappearance of MDZ from the SCHH system was plotted over time. Data are from a single experiment with treatments performed in triplicate wells. Mean values are reported ± S.D.

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    Fig. 6.

    Intrinsic clearance of MDZ was calculated from linear regression analysis of the percentage of parent remaining (log transformed) versus time profile to estimate the elimination rate. MDZ intrinsic clearance in SCHH treated with SJW (A), RIF (A), SSE (B), or SCE (B) for 72 hour. *P value ≤0.05 when compared with solvent control. Data are from a single experiment with treatments performed in triplicate wells. Mean values reported ± S.D.

Tables

  • Figures
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    TABLE 1

    Transporter Certified Cryopreserved Hepatocytes

    Hepatocyte LotSexExperimentFigure
    HUM4059Female24-hour cytotoxicity assessmentFig. 1A
    HUM4075BMale72-hour cytotoxicity assessmentFig. 1B
    HUM4059FemaleCYP3A4/5 inhibition evaluationFig. 2
    HUM4109FemaleCYP3A4 mRNA induction assessmentFig. 3
    HUM4122CMaleIntracellular concentration evaluationFig. 4
    HUM4122CMaleMDZ intrinsic clearance studiesFigs. 5 and 6
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Drug Metabolism and Disposition: 45 (9)
Drug Metabolism and Disposition
Vol. 45, Issue 9
1 Sep 2017
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Research ArticleArticle

In Vitro Prediction of Clinical Herb-Drug Interactions

Jonathan P. Jackson, Kimberly M. Freeman, Weslyn W. Friley, Ashley G. Herman, Christopher B. Black, Kenneth R. Brouwer and Amy L. Roe
Drug Metabolism and Disposition September 1, 2017, 45 (9) 1019-1026; DOI: https://doi.org/10.1124/dmd.117.075408

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Research ArticleArticle

In Vitro Prediction of Clinical Herb-Drug Interactions

Jonathan P. Jackson, Kimberly M. Freeman, Weslyn W. Friley, Ashley G. Herman, Christopher B. Black, Kenneth R. Brouwer and Amy L. Roe
Drug Metabolism and Disposition September 1, 2017, 45 (9) 1019-1026; DOI: https://doi.org/10.1124/dmd.117.075408
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