PT  - JOURNAL ARTICLE
AU  - Masashi Honda
AU  - Yuka Muroi
AU  - Yuichiro Tamaki
AU  - Daisuke Saigusa
AU  - Naoto Suzuki
AU  - Yoshihisa Tomioka
AU  - Yoichi Matsubara
AU  - Akifumi Oda
AU  - Noriyasu Hirasawa
AU  - Masahiro Hiratsuka
TI  - Functional Characterization of CYP2B6 Allelic Variants in Demethylation of Antimalarial Artemether
AID  - 10.1124/dmd.111.040352
DP  - 2011 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1860--1865
VI  - 39
IP  - 10
4099  - http://dmd.aspetjournals.org/content/39/10/1860.short
4100  - http://dmd.aspetjournals.org/content/39/10/1860.full
SO  - Drug Metab Dispos2011 Oct 01; 39
AB  - 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.