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Research ArticleArticle

Stereospecific Metabolism of Itraconazole by CYP3A4: Dioxolane Ring Scission of Azole Antifungals

Chi-Chi Peng, Wei Shi, Justin D. Lutz, Kent L. Kunze, Jun O. Liu, Wendel L. Nelson and Nina Isoherranen
Drug Metabolism and Disposition March 2012, 40 (3) 426-435; DOI: https://doi.org/10.1124/dmd.111.042739
Chi-Chi Peng
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Wei Shi
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Justin D. Lutz
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Kent L. Kunze
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Jun O. Liu
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Wendel L. Nelson
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Nina Isoherranen
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Abstract

Itraconazole (ITZ) is a mixture of four cis-stereoisomers that inhibit CYP3A4 potently and coordinate CYP3A4 heme via the triazole nitrogen. However, (2R,4S,2′R)-ITZ and (2R,4S,2′S)-ITZ also undergo stereoselective sequential metabolism by CYP3A4 at a site distant from the triazole ring to 3′-OH-ITZ, keto-ITZ, and N-desalkyl-ITZ. This stereoselective metabolism demonstrates specific interactions of ITZ within the CYP3A4 active site. To further investigate this process, the binding and metabolism of the four trans-ITZ stereoisomers by CYP3A4 were characterized. All four trans-ITZ stereoisomers were tight binding inhibitors of CYP3A4-mediated midazolam hydroxylation (IC50 16–26 nM), and each gave a type II spectrum upon binding to CYP3A4. However, instead of formation of 3′-OH-ITZ, they were oxidized at the dioxolane ring, leading to ring scission and formation of two new metabolites of ITZ. These two metabolites were also formed from the four cis-ITZ stereoisomers, although not as efficiently. The catalytic rates of dioxolane ring scission were similar to the dissociation rates of ITZ stereoisomers from CYP3A4, suggesting that the heme iron is reduced while the triazole moiety coordinates to it and no dissociation of ITZ is necessary before catalysis. The triazole containing metabolite [1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone] also inhibited CYP3A4 (IC50 >15 μM) and showed type II binding with CYP3A4. The dioxolane ring scission appears to be clinically relevant because this metabolite was detected in urine samples from subjects that had been administered the mixture of cis-ITZ isomers. These data suggest that the dioxolane ring scission is a metabolic pathway for drugs that contain this moiety.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant P01-GM32165] (to N.I., K.L.K., and W.L.N.); and the National Institutes of Health National Cancer Institute [Grant CA122814] (to J.O.L.).

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

    http://dx.doi.org/10.1124/dmd.111.042739.

  • ABBREVIATIONS:

    ITZ
    itraconazole
    P450
    cytochrome P450
    DDI
    drug-drug interactions
    SPR
    surface plasmon resonance
    HPLC
    high-performance liquid chromatography
    ACN
    acetonitrile
    LC/MS
    liquid chromatography/mass spectrometry
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    HLM
    human liver microsomes
    KPi
    potassium phosphate
    MDZ
    midazolam
    QToa-TOF
    Quadrupole/Triwave/Orthogonal acceleration time-of-flight tandem hybrid mass spectrometer
    OH-MDZ
    1′-hydroxymidazolam
    EI
    enzyme inhibitor
    RU
    relative response units.

  • Received September 13, 2011.
  • Accepted November 18, 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

DIOXOLANE RING SCISSION OF ITRACONAZOLE BY CYP3A4

Chi-Chi Peng, Wei Shi, Justin D. Lutz, Kent L. Kunze, Jun O. Liu, Wendel L. Nelson and Nina Isoherranen
Drug Metabolism and Disposition March 1, 2012, 40 (3) 426-435; DOI: https://doi.org/10.1124/dmd.111.042739

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Research ArticleArticle

DIOXOLANE RING SCISSION OF ITRACONAZOLE BY CYP3A4

Chi-Chi Peng, Wei Shi, Justin D. Lutz, Kent L. Kunze, Jun O. Liu, Wendel L. Nelson and Nina Isoherranen
Drug Metabolism and Disposition March 1, 2012, 40 (3) 426-435; DOI: https://doi.org/10.1124/dmd.111.042739
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