Functional characterization of CYP2B6 allelic variants in demethylation of antimalarial artemether
Language: 
English
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 (V(max)/K(m)) 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 V(max), and 3 variants (CYP2B6.14, CYP2B6.20 and CYP2B6.27) exhibited significantly lower V(max) compared with that of CYP2B6.1. This functional analysis of CYP2B6 variants could provide useful information for individualization of antimalarial drug therapy.

Author(s): 
Honda, Masashi
Muroi, Yuka
Tamaki, Yuichiro
Saigusa, Daisuke
Suzuki, Naoto
Tomioka, Yoshihisa
Matsubara, Yoichi
Oda, Akifumi
Hirasawa, Noriyasu
Hiratsuka, Masahiro
Item Type: 
Journal Article
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals
Journal Abbreviation: 
Drug Metab. Dispos.
Publication Date: 
10/11/2015
Publication Year: 
2011
Pages: 
1860-1865
Volume: 
39
Issue: 
10
ISSN: 
1521-009X
DOI: 
10.1124/dmd.111.040352
Library Catalog: 
PubMed
Extra: 
PMID: 21746968

Turabian/Chicago Citation

Masashi Honda, Yuka Muroi, Yuichiro Tamaki, Daisuke Saigusa, Naoto Suzuki, Yoshihisa Tomioka, Yoichi Matsubara, Akifumi Oda, Noriyasu Hirasawa and Masahiro Hiratsuka. 10/11/2015. "Functional characterization of CYP2B6 allelic variants in demethylation of antimalarial artemether." Drug Metabolism and Disposition: The Biological Fate of Chemicals 39: 10: 1860-1865. 10.1124/dmd.111.040352.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1124/dmd.111.040352 | issn = 1521-009X | volume = 39 | pages = 1860-1865 | last = Honda | first = Masashi | coauthors = Muroi, Yuka, Tamaki, Yuichiro, Saigusa, Daisuke, Suzuki, Naoto, Tomioka, Yoshihisa, Matsubara, Yoichi, Oda, Akifumi, Hirasawa, Noriyasu, Hiratsuka, Masahiro | title = Functional characterization of CYP2B6 allelic variants in demethylation of antimalarial artemether | journal = Drug Metabolism and Disposition: The Biological Fate of Chemicals | date = 10/11/2015 | pmid = | pmc = }} </ref>