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Research ArticleArticle

Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether

Masashi Honda, Yuka Muroi, Yuichiro Tamaki, Daisuke Saigusa, Naoto Suzuki, Yoshihisa Tomioka, Yoichi Matsubara, Akifumi Oda, Noriyasu Hirasawa and Masahiro Hiratsuka
Drug Metabolism and Disposition October 2011, 39 (10) 1860-1865; DOI: https://doi.org/10.1124/dmd.111.040352
Masashi Honda
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Yuka Muroi
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Yuichiro Tamaki
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Daisuke Saigusa
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Naoto Suzuki
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Yoshihisa Tomioka
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Yoichi Matsubara
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Akifumi Oda
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Noriyasu Hirasawa
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Masahiro Hiratsuka
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Abstract

Artemether (AM) is one of the most effective antimalarial drugs. The elimination half-life of AM is very short, and it shows large interindividual variability in pharmacokinetic parameters. The aim of this study was to identify cytochrome P450 (P450) isozymes responsible for the demethylation of AM and to evaluate functional differences between 26 CYP2B6 allelic variants in vitro. Of 14 recombinant P450s examined in this study, CYP2B6 and CYP3A4 were primarily responsible for production of the desmethyl metabolite dihydroartemisinin. The intrinsic clearance (Vmax/Km) of CYP2B6 was 6-fold higher than that of CYP3A4. AM demethylation activity was correlated with CYP2B6 protein levels (P = 0.004); however, it was not correlated with CYP3A4 protein levels (P = 0.27) in human liver microsomes. Wild-type CYP2B6.1 and 25 CYP2B6 allelic variants (CYP2B6.2-CYP2B6.21 and CYP2B6.23-CYP2B6.27) were heterologously expressed in COS-7 cells. In vitro analysis revealed no enzymatic activity in 5 variants (CYP2B6.8, CYP2B6.12, CYP2B6.18, CYP2B6.21, and CYP2B6.24), lower activity in 7 variants (CYP2B6.10, CYP2B6.11, CYP2B6.14, CYP2B6.15, CYP2B6.16, CYP2B6.20, and CYP2B6.27), and higher activity in 4 variants (CYP2B6.2, CYP2B6.4, CYP2B6.6, and CYP2B6.19), compared with that of wild-type CYP2B6.1. In kinetic analysis, 3 variants (CYP2B6.2, CYP2B6.4, and CYP2B6.6) exhibited significantly higher Vmax, and 3 variants (CYP2B6.14, CYP2B6.20 and CYP2B6.27) exhibited significantly lower Vmax compared with that of CYP2B6.1. This functional analysis of CYP2B6 variants could provide useful information for individualization of antimalarial drug therapy.

Footnotes

  • This work was supported by the Japan Society for the Promotion of Science [KAKENHI 20590154] and in part by the Smoking Research Foundation.

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

    doi:10.1124/dmd.111.040352.

  • ABBREVIATIONS:

    AM
    artemether
    DHA
    dihydroartemisinin
    P450
    cytochrome P450
    ART
    artemisinin
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry.

  • Received May 5, 2011.
  • Accepted July 11, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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Research ArticleArticle

DEMETHYLATION OF ANTIMALARIAL ARTEMETHER BY CYP2B6 VARIANTS

Masashi Honda, Yuka Muroi, Yuichiro Tamaki, Daisuke Saigusa, Naoto Suzuki, Yoshihisa Tomioka, Yoichi Matsubara, Akifumi Oda, Noriyasu Hirasawa and Masahiro Hiratsuka
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1860-1865; DOI: https://doi.org/10.1124/dmd.111.040352

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Research ArticleArticle

DEMETHYLATION OF ANTIMALARIAL ARTEMETHER BY CYP2B6 VARIANTS

Masashi Honda, Yuka Muroi, Yuichiro Tamaki, Daisuke Saigusa, Naoto Suzuki, Yoshihisa Tomioka, Yoichi Matsubara, Akifumi Oda, Noriyasu Hirasawa and Masahiro Hiratsuka
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1860-1865; DOI: https://doi.org/10.1124/dmd.111.040352
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