|
KMID : 0043320150380112083
|
|
Archives of Pharmacal Research
2015 Volume.38 No. 11 p.2083 ~ p.2091
|
|
|
Effects of the CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites
|
|
Byeon Ji-Yeong
Kim Young-Hoon
Na Han-Sung
Jang Jong-Hwa
Kim Se-Hyung
Lee Yun-Jeong
Bae Jung-Woo
Kim In-Su
Jang Choon-Gon
Chung Myeon-Woo
Lee Seok-Yong
|
|
|
Abstract
|
|
|
|
To investigate the effect of the variant CYP2D6*10 allele on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine (4-HAT) and N-desmethylatomoxetine (NAT), in healthy subjects, a single oral dose of atomoxetine was administered to 62 subjects with a CYP2D6*wt/*wt (*wt = *1 or *2, n = 22), CYP2D6*wt/*10 (n = 22) or CYP2D6*10/*10 (n = 18) genotype. Plasma samples were then collected for 24 h after atomoxetine administration. The concentrations of atomoxetine and its metabolites were assayed using LC?MS/MS. For atomoxetine, the Cmax, AUC0?∞, t1/2 and CL/F showed genotype-dependent differences. The CYP2D6*10/*10 and CYP2D6*wt/*10 groups showed 1.74- and 1.15-fold higher Cmax, 3.40- and 1.33-fold higher AUC0?∞, and 69.7 and 24.6 % lower CL/F, compared to those of the CYP2D6*wt/*wt group, respectively. The Cmax and t1/2 for 4-HAT were lower and longer in the CYP2D6*10/*10 group than those in the CYP2D6*wt/*wt group, but the AUC0?∞ was not different between these groups. The Cmax, AUC0?∞ and t1/2 for NAT were profoundly greater in the CYP2D6*10/*10 group than they were in the CYP2D6*wt/*wt group. The concentration of active moieties of atomoxetine (atomoxetine + 4-HAT) in the CYP2D6*10/*10 group was 3.32-fold higher than that in the CYP2D6*wt/*wt group. The mean exposure to active moieties of atomoxetine was markedly higher in subjects with the CYP2D6*10/*10 genotype compared to that in those with the CYP2D6*wt/*wt genotype. The higher systemic exposure of the active atomoxetine moieties in CYP2D6*10/*10 individuals may increase the risk of concentration-related adverse events of atomoxetine, although this has not yet been clinically confirmed.
|
|
|
KEYWORD
|
|
|
Atomoxetine, CYP2D6*10, Pharmacokinetics, 4-hydroxyatomoxetine
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
  
|
|