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21. Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metabolite

Author

Kim, Se-Hyung, primary, Kim, Do-Hoon, additional, Byeon, Ji-Yeong, additional, Kim, Young-Hoon, additional, Kim, Dong-Hyun, additional, Lim, Hye-Jin, additional, Lee, Choong-Min, additional, Whang, Sang Sup, additional, Choi, Chang-Ik, additional, Bae, Jung-Woo, additional, Lee, Yun Jeong, additional, Jang, Choon-Gon, additional, and Lee, Seok-Yong, additional

Published
2016
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22. Effect of the <italic>CYP2D6*10</italic> allele on the pharmacokinetics of clomiphene and its active metabolites.

Author

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, and 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. [ABSTRACT FROM AUTHOR]

Published
2018
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