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Research ArticleArticle

Efavirenz Primary and Secondary Metabolism In Vitro and In Vivo: Identification of Novel Metabolic Pathways and Cytochrome P450 2A6 as the Principal Catalyst of Efavirenz 7-Hydroxylation

Evan T. Ogburn, David R. Jones, Andrea R. Masters, Cong Xu, Yingying Guo and Zeruesenay Desta
Drug Metabolism and Disposition July 2010, 38 (7) 1218-1229; DOI: https://doi.org/10.1124/dmd.109.031393
Evan T. Ogburn
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David R. Jones
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Andrea R. Masters
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Cong Xu
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Yingying Guo
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Zeruesenay Desta
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Abstract

Efavirenz primary and secondary metabolism was investigated in vitro and in vivo. In human liver microsome (HLM) samples, 7- and 8-hydroxyefavirenz accounted for 22.5 and 77.5% of the overall efavirenz metabolism, respectively. Kinetic, inhibition, and correlation analyses in HLM samples and experiments in expressed cytochrome P450 show that CYP2A6 is the principal catalyst of efavirenz 7-hydroxylation. Although CYP2B6 was the main enzyme catalyzing efavirenz 8-hydroxylation, CYP2A6 also seems to contribute. Both 7- and 8-hydroxyefavirenz were further oxidized to novel dihydroxylated metabolite(s) primarily by CYP2B6. These dihydroxylated metabolite(s) were not the same as 8,14-dihydroxyefavirenz, a metabolite that has been suggested to be directly formed via 14-hydroxylation of 8-hydroxyefavirenz, because 8,14-dihydroxyefavirenz was not detected in vitro when efavirenz, 7-, or 8-hydroxyefavirenz were used as substrates. Efavirenz and its primary and secondary metabolites that were identified in vitro were quantified in plasma samples obtained from subjects taking a single 600-mg oral dose of efavirenz. 8,14-Dihydroxyefavirenz was detected and quantified in these plasma samples, suggesting that the glucuronide or the sulfate of 8-hydroxyefavirenz might undergo 14-hydroxylation in vivo. In conclusion, efavirenz metabolism is complex, involving unique and novel secondary metabolism. Although efavirenz 8-hydroxylation by CYP2B6 remains the major clearance mechanism of efavirenz, CYP2A6-mediated 7-hydroxylation (and to some extent 8-hydroxylation) may also contribute. Efavirenz may be a valuable dual phenotyping tool to study CYP2B6 and CYP2A6, and this should be further tested in vivo.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants GM078501, GM067308].

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

    doi:10.1124/dmd.109.031393.

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

  • ABBREVIATIONS:

    P450
    cytochrome P450
    HLM
    human liver microsome
    HPLC
    high-performance liquid chromatography
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    MRM
    multiple reaction monitoring
    MS
    mass spectrometry
    CLint
    intrinsic clearance
    AUC0–72
    plasma area under the plasma concentration-time curve.

  • Received December 1, 2009.
  • Accepted March 24, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (7)
Drug Metabolism and Disposition
Vol. 38, Issue 7
1 Jul 2010
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Research ArticleArticle

Efavirenz Primary and Secondary Metabolism In Vitro and In Vivo: Identification of Novel Metabolic Pathways and Cytochrome P450 2A6 as the Principal Catalyst of Efavirenz 7-Hydroxylation

Evan T. Ogburn, David R. Jones, Andrea R. Masters, Cong Xu, Yingying Guo and Zeruesenay Desta
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1218-1229; DOI: https://doi.org/10.1124/dmd.109.031393

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Research ArticleArticle

Efavirenz Primary and Secondary Metabolism In Vitro and In Vivo: Identification of Novel Metabolic Pathways and Cytochrome P450 2A6 as the Principal Catalyst of Efavirenz 7-Hydroxylation

Evan T. Ogburn, David R. Jones, Andrea R. Masters, Cong Xu, Yingying Guo and Zeruesenay Desta
Drug Metabolism and Disposition July 1, 2010, 38 (7) 1218-1229; DOI: https://doi.org/10.1124/dmd.109.031393
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