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Research ArticleArticle

Use of a Multistaged Time-Dependent Inhibition Assay to Assess the Impact of Intestinal Metabolism on Drug-Drug Interaction Potential

Michael Zientek and Deepak Dalvie
Drug Metabolism and Disposition March 2012, 40 (3) 467-473; DOI: https://doi.org/10.1124/dmd.111.043257
Michael Zientek
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Deepak Dalvie
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Abstract

In early discovery, compounds are often eliminated because of their potential to undergo metabolic activation and/or cytochrome P450 time-dependent inactivation (TDI). The blockbuster drug raloxifene is an example of a compound that would have been eliminated in the current paradigm. Despite raloxifene's in vitro bioactivation and TDI of CYP3A4, it is well tolerated in patients with no drug-drug interactions. This discordance is attributed to its presystemic glucuronidation, thereby decreasing the amount of unchanged raloxifene available for CYP3A inactivation. The current study used raloxifene as a model to assess the effect of hepatic and intestinal glucuronidation on the kinetic parameters of CYP3A4 inactivation. Therefore, a simple multistaged time-dependent inactivation using UDP-glucuronosyltransferase-enabled and -absent reactions was built to understand the impact of the gut metabolism on inactivation potential. The results of these experiments demonstrated a 2.7-fold change in inactivation efficiency of CYP3A4. Incorporation of these results into a simulated midazolam drug-drug interaction study showed very little change in the pharmacokinetic parameters of the victim drug. In contrast, the absence of glucuronidation resulted in a 4.1-fold increase in the area under the curve (AUC) of midazolam, when in the presence of raloxifene, hence providing an understanding of the impact of intestinal glucuronidation on raloxifene's time-dependent inhibition of CYP3A4 and also providing a validation of a simple in vitro experiment to assess the influence of gut metabolism on time-dependent inhibitors at the discovery phase.

Footnotes

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

    http://dx.doi.org/10.1124/dmd.111.043257.

  • ABBREVIATIONS:

    TDI
    time-dependent inactivation
    P450
    cytochrome P450
    UDPGA
    UDP-glucuronic acid
    DDI
    drug-drug interaction
    HLM
    human liver microsomes
    UGT
    UDP glucuronosyltransferase
    AUC
    area under the curve
    PK
    pharmacokinetic
    HIM
    human intestinal microsomes.

  • Received October 7, 2011.
  • Accepted November 23, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (3)
Drug Metabolism and Disposition
Vol. 40, Issue 3
1 Mar 2012
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Research ArticleArticle

IMPACT OF SEQUENTIAL METABOLISM ON TIME-DEPENDENT INHIBITION

Michael Zientek and Deepak Dalvie
Drug Metabolism and Disposition March 1, 2012, 40 (3) 467-473; DOI: https://doi.org/10.1124/dmd.111.043257

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Research ArticleArticle

IMPACT OF SEQUENTIAL METABOLISM ON TIME-DEPENDENT INHIBITION

Michael Zientek and Deepak Dalvie
Drug Metabolism and Disposition March 1, 2012, 40 (3) 467-473; DOI: https://doi.org/10.1124/dmd.111.043257
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