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Research ArticleArticle

Prediction of CYP3A-Mediated Drug-Drug Interactions Using Human Hepatocytes Suspended in Human Plasma

Jialin Mao, Michael A. Mohutsky, John P. Harrelson, Steven A. Wrighton and Stephen D. Hall
Drug Metabolism and Disposition April 2011, 39 (4) 591-602; DOI: https://doi.org/10.1124/dmd.110.036400
Jialin Mao
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Michael A. Mohutsky
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John P. Harrelson
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Steven A. Wrighton
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Stephen D. Hall
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Cryopreserved human hepatocytes suspended in human plasma (HHSHP) represent an integrated metabolic environment for predicting drug-drug interactions (DDIs). In this study, 13 CYP3A reversible and/or time-dependent inhibitors (TDIs) were incubated with HHSHP for 20 min over a range of concentrations after which midazolam 1′-hydroxylation was used to measure CYP3A activity. This single incubation time method yielded IC50 values for the 13 inhibitors. For each CYP3A inhibitor-victim drug pair, the IC50 value was combined with total average plasma concentration of the inhibitor in humans, fraction of the victim drug cleared by CYP3A, and intestinal availability of the victim drug to predict the ratio of plasma area under the curve of the victim drug in the presence and absence of inhibitor. Of 52 clinical DDI studies using these 13 inhibitors identified in the literature, 85% were predicted by this method within 2-fold of the observed change, and all were predicted within 3-fold. Subsequent studies to determine mechanism (reversible and time-dependent inhibitors) were performed by using a range of incubation periods and inhibitor concentrations. This system differentiated among reversible inhibitors, TDIs, and the combination of both. When the reversible and inactivation parameters were incorporated into predictive models, 65% of 52 clinical DDIs were predicted within 2-fold of the observed changes and 88% were within 3-fold. Thus, HHSHP produced accurate DDI predictions with a simple IC50 determined at a single incubation time regardless of the inhibition mechanism; further if needed, the mechanism(s) of inhibition can be identified.

Footnotes

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

    doi:10.1124/dmd.110.036400.

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

  • ABBREVIATIONS:

    DDI
    drug-drug interaction
    HLM
    human liver microsome(s)
    P450
    cytochrome P450
    HHSHP
    human hepatocytes suspended in human plasma
    AUC
    area under the curve
    OH
    hydroxy
    CV
    coefficient of variation
    TDI
    time-dependent inhibitor
    TAO
    troleandomycin.

  • Received September 20, 2010.
  • Accepted January 6, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (4)
Drug Metabolism and Disposition
Vol. 39, Issue 4
1 Apr 2011
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Research ArticleArticle

Prediction of CYP3A-Mediated Drug-Drug Interactions Using Human Hepatocytes Suspended in Human Plasma

Jialin Mao, Michael A. Mohutsky, John P. Harrelson, Steven A. Wrighton and Stephen D. Hall
Drug Metabolism and Disposition April 1, 2011, 39 (4) 591-602; DOI: https://doi.org/10.1124/dmd.110.036400

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Research ArticleArticle

Prediction of CYP3A-Mediated Drug-Drug Interactions Using Human Hepatocytes Suspended in Human Plasma

Jialin Mao, Michael A. Mohutsky, John P. Harrelson, Steven A. Wrighton and Stephen D. Hall
Drug Metabolism and Disposition April 1, 2011, 39 (4) 591-602; DOI: https://doi.org/10.1124/dmd.110.036400
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