|
KMID : 0043320180410030347
|
|
Archives of Pharmacal Research
2018 Volume.41 No. 3 p.347 ~ p.353
|
|
|
Effect of the CYP2D6*10 allele on the pharmacokinetics of clomiphene and its active metabolites
|
|
Kim Mi-Jung
Byeon Ji-Yeong
Kim Young-Hoon
Kim Se-Hyung
Lee Choong-Min
Jung Eui-Hyun
Chae Won-Ki
Lee Yun-Jeong
Jang Choon-Gon
Lee Seok-Yong
Choi Chang-Ik
|
|
|
Abstract
|
|
|
|
Clomiphene citrate, a selective estrogen receptor modulator, is metabolized into its 4-hydroxylated active metabolites, primarily by CYP2D6. In this study, we investigated the effects of the most common CYP2D6 variant allele in Asians, CYP2D6*10, on the pharmacokinetics of clomiphene and its two active metabolites (4-OH-CLO and 4-OH-DE-CLO) in healthy Korean subjects. A single 50-mg oral dose of clomiphene citrate was given to 22 Korean subjects divided into three genotype groups according to CYP2D6 genotypes, CYP2D6*wt/*wt (n = 8; *wt = *1 or *2), CYP2D6*wt/*10 (n = 8) and CYP2D6*10/*10 (n = 6). Concentrations of clomiphene and its metabolites were determined using a validated HPLC?MS/MS analytical method in plasma samples collected up to 168 h after the drug intake. There was a significant difference only in the Cmax of clomiphene between three CYP2D6 genotype groups (p < 0.05). Paradoxically, the elimination half-life (t1/2) and AUC of both active metabolites were all significantly increased in the CYP2D6*10 homozygous carriers, compared with other genotype groups (all p < 0.001). The AUCinf of corrected clomiphene active moiety in CYP2D6*10/*10 subjects was 2.95- and 2.05-fold higher than that of CYP2D6*wt/*wt and *wt/*10 genotype groups, respectively (both p < 0.001). Along with the partial impacts on the biotransformation of clomiphene and its metabolites by CYP2D6 genetic polymorphism, further studies on the effects of other CYP enzymes in a multiple-dosing condition can provide more definite evidence for the inter-individual variabilities in clomiphene pharmacokinetics and/or drug response.
|
|
|
KEYWORD
|
|
|
Clomiphene, CYP2D6, Genetic polymorphism, Pharmacokinetics, Metabolism
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
  
|
|