Effect of the CYP2D6*10 allele on the pharmacokinetics of clomiphene and its active metabolites.

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, CYP2D610, 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, CYP2D6wt/*wt (n = 8; *wt = 1 or 2), CYP2D6wt/10 (n = 8) and CYP2D610/10 (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 C of clomiphene between three CYP2D6 genotype groups (p < 0.05). Paradoxically, the elimination half-life (t) and AUC of both active metabolites were all significantly increased in the CYP2D610 homozygous carriers, compared with other genotype groups (all p < 0.001). The AUC of corrected clomiphene active moiety in CYP2D610/10 subjects was 2.95- and 2.05-fold higher than that of CYP2D6wt/*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.