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Research ArticleArticle

Biotransformation of the Antiretroviral Drug Etravirine: Metabolite Identification, Reaction Phenotyping, and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism

Lindsay J. Yanakakis and Namandjé N. Bumpus
Drug Metabolism and Disposition April 2012, 40 (4) 803-814; DOI: https://doi.org/10.1124/dmd.111.044404
Lindsay J. Yanakakis
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Namandjé N. Bumpus
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Abstract

Etravirine (ETR) is a second-generation non-nucleoside reverse transcriptase inhibitor prescribed for the treatment of HIV-1. By using human liver microsomes (HLMs), cDNA-expressed cytochromes P450 (P450s), and UDP-glucuronosyltransferases (UGTs), the routes of ETR metabolism were defined. Incubations with cDNA-expressed P450 isozymes and chemical inhibition studies using HLMs indicated that CYP2C19 is primarily responsible for the formation of both the major monohydroxylated and dihydroxylated metabolites of ETR. Tandem mass spectrometry suggested that these metabolites were produced via monomethylhydroxylation and dimethylhydroxylation of the dimethylbenzonitrile moiety. Formation of these monohydroxy and dihydroxy metabolites was decreased by 75 and 100%, respectively, in assays performed using HLMs that were genotyped as homozygous for the loss-of-function CYP2C19*2 allele compared with formation by HLMs genotyped as CYP2C19*1/*1. Two monohydroxylated metabolites of lower abundance were formed by CYP3A4, and interestingly, although CYP2C9 showed no activity toward the parent compound, this enzyme appeared to act in concert with CYP3A4 to form two minor dihydroxylated products of ETR. UGT1A3 and UGT1A8 were demonstrated to glucuronidate a CYP3A4-dependent monohydroxylated product. In addition, treatment of primary human hepatocytes with ETR resulted in 3.2-, 5.2-, 11.8-, and 17.9-fold increases in CYP3A4 mRNA levels 6, 12, 24, and 72 h after treatment. The presence of the pregnane X receptor antagonist sulforaphane blocked the ETR-mediated increase in CYP3A4 mRNA expression. Taken together, these data suggest that ETR and ETR metabolites are substrates of CYP2C19, CYP3A4, CYP2C9, UGT1A3, and UGT1A8 and that ETR is a PXR-dependent modulator of CYP3A4 mRNA levels.

Footnotes

  • This work was supported by the PhRMA Foundation (Research Starter Grant in Pharmacology/Toxicology; to N.N.B.). The AB SCIEX QTRAP 5500 mass spectrometer was purchased using a grant from the National Institutes of Health National Center for Research Resources [Grant 1S10-RR27733]; the Waters Acquity ultraperformance liquid chromatograph interfaced with the AB SCIEX QTRAP 5500 mass spectrometer was purchased with funds provided by the Pendleton Foundation Trust.

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

    http://dx.doi.org/10.1124/dmd.111.044404.

  • ABBREVIATIONS:

    HIV
    human immunodeficiency virus
    NNRTI
    non-nucleoside reverse transcriptase inhibitor
    ETR
    etravirine
    P450
    cytochrome P450
    UGT
    UDP-glucuronosyltransferase
    HLM
    human liver microsomes
    PXR
    pregnane X receptor
    PPP
    2-phenyl-2-(1-piperidinyl)propane
    SFN
    sulforaphane
    RIF
    rifampin
    UDPGA
    UDP-glucuronic acid
    UPLC-MS
    ultraperformance liquid chromatography-mass spectrometry
    DMSO
    dimethyl sulfoxide
    TIS
    TurboIonSpray
    MS/MS
    tandem mass spectrometry
    PCR
    polymerase chain reaction
    qPCR
    quantitative polymerase chain reaction
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase.

  • Received December 20, 2011.
  • Accepted January 23, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
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Research ArticleArticle

IN VITRO METABOLISM OF ETRAVIRINE

Lindsay J. Yanakakis and Namandjé N. Bumpus
Drug Metabolism and Disposition April 1, 2012, 40 (4) 803-814; DOI: https://doi.org/10.1124/dmd.111.044404

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Research ArticleArticle

IN VITRO METABOLISM OF ETRAVIRINE

Lindsay J. Yanakakis and Namandjé N. Bumpus
Drug Metabolism and Disposition April 1, 2012, 40 (4) 803-814; DOI: https://doi.org/10.1124/dmd.111.044404
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