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Research ArticleArticle

Determination of Time-Dependent Inactivation of CYP3A4 in Cryopreserved Human Hepatocytes and Assessment of Human Drug-Drug Interactions

Yuan Chen, Liling Liu, Mario Monshouwer and Adrian J. Fretland
Drug Metabolism and Disposition November 2011, 39 (11) 2085-2092; DOI: https://doi.org/10.1124/dmd.111.040634
Yuan Chen
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Liling Liu
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Mario Monshouwer
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Adrian J. Fretland
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Abstract

Assessment of time-dependent inhibition (TDI), especially CYP3A4, is an important parameter for preclinical and clinical development. The use of human liver microsomes (HLM) is the most common in vitro matrix to assess TDI, but this often leads to an overprediction of an actual effect observed clinically. Recently, the use of human hepatocytes has been hypothesized as a more relevant and possibly predictive matrix for the assessment of CYP3A4 TDI. Our work evaluates and optimizes three different human hepatocyte assays for the assessment of CYP3A4 TDI using pooled cryopreserved human hepatocytes. Using two of the optimized methods, the time-dependent inhibition kinetic parameters (KI and kinact) for four known CYP3A4 TDI (diltiazem, erythromycin, verapamil, and troleandomycin) were determined. When comparing TDI in HLM, the KI values from hepatocytes were in general 4- to 13-fold higher than that in HLM, whereas the kinact values in human hepatocytes were similar or slightly higher or lower depending on the inhibitor. The inactivation potency (kinact/KI) for four tested CYP3A4 inactivators in human hepatocytes was generally lower than that in HLM due to either lower affinity (KI) or lower inactivation rate (kinact) or both. When drug interactions were simulated with Simcyp using either HLM or human hepatocyte data, the predictions using the kinetic parameters from human hepatocytes resulted in a much better simulated change in pharmacokinetics compared with observed clinical data.

Footnotes

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

    doi:10.1124/dmd.111.040634.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    TDI
    time-dependent inhibition (or inhibitor)
    DDI
    drug-drug interactions
    ACN
    acetonitrile
    HLM
    human liver microsomes
    HH
    human hepatocytes
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    TAO
    troleandomycin
    AUC
    area under the curve
    PBPK
    physiologically based pharmacokinetics
    HPLC
    high-performance liquid chromatography
    FBS
    fetal bovine serum
    GMFE
    geometric mean-fold error
    RMSE
    root mean square error
    MRS
    mean residual sum
    KI
    inhibitor concentration that supports half the maximal rate of inactivation
    kinact
    maximal rate of enzyme inactivation.

  • Received May 17, 2011.
  • Accepted August 11, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (11)
Drug Metabolism and Disposition
Vol. 39, Issue 11
1 Nov 2011
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Research ArticleArticle

ASSESSMENT OF CYP3A4 TDI IN HEPATOCYTES AND HUMAN DDI

Yuan Chen, Liling Liu, Mario Monshouwer and Adrian J. Fretland
Drug Metabolism and Disposition November 1, 2011, 39 (11) 2085-2092; DOI: https://doi.org/10.1124/dmd.111.040634

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Research ArticleArticle

ASSESSMENT OF CYP3A4 TDI IN HEPATOCYTES AND HUMAN DDI

Yuan Chen, Liling Liu, Mario Monshouwer and Adrian J. Fretland
Drug Metabolism and Disposition November 1, 2011, 39 (11) 2085-2092; DOI: https://doi.org/10.1124/dmd.111.040634
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