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Research ArticleArticle

In Vitro Evaluation of the Interaction Potential of Irosustat with Drug-Metabolizing Enzymes

Verònica Ventura, Josep Solà, Concepción Peraire, Françoise Brée and Rosendo Obach
Drug Metabolism and Disposition July 2012, 40 (7) 1268-1278; DOI: https://doi.org/10.1124/dmd.111.044271
Verònica Ventura
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Josep Solà
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Concepción Peraire
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Françoise Brée
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Rosendo Obach
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Abstract

Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. To predict clinical drug-drug interactions between irosustat and possible concomitantly administered medications, the inhibition/induction potential of irosustat with the main drug-metabolizing enzymes was investigated in vitro. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied. Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a Ki of 0.77 μM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (Ki = 5.8 μM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.

Footnotes

  • This work was sponsored by the Ipsen Group.

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

    http://dx.doi.org/10.1124/dmd.111.044271.

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

  • ABBREVIATIONS:

    STS
    steroid sulfatase
    AI
    aromatase inhibitor
    Cmax,ss
    steady-state maximal plasma concentration
    CT
    threshold cycle
    DDI
    drug-drug interaction
    DMSO
    dimethyl sulfoxide
    HLM
    human liver microsomes
    HPLC
    high-performance liquid chromatography
    P450
    cytochrome P450
    PCR
    polymerase chain reaction
    RT
    reverse transcription
    TDI
    time-dependent inhibition
    UGT
    UDP-glucuronosyltransferase.

  • Received December 11, 2011.
  • Accepted March 26, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (7)
Drug Metabolism and Disposition
Vol. 40, Issue 7
1 Jul 2012
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Research ArticleArticle

METABOLIC DRUG-DRUG INTERACTIONS OF IROSUSTAT

Verònica Ventura, Josep Solà, Concepción Peraire, Françoise Brée and Rosendo Obach
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1268-1278; DOI: https://doi.org/10.1124/dmd.111.044271

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Research ArticleArticle

METABOLIC DRUG-DRUG INTERACTIONS OF IROSUSTAT

Verònica Ventura, Josep Solà, Concepción Peraire, Françoise Brée and Rosendo Obach
Drug Metabolism and Disposition July 1, 2012, 40 (7) 1268-1278; DOI: https://doi.org/10.1124/dmd.111.044271
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