School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
College of Pharmacy, Dankook University, Cheonan, 31116, Republic of Korea.
Arch Pharm Res. 2018 Mar;41(3):347-353. doi: 10.1007/s12272-018-1005-7. Epub 2018 Mar 7.
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.
枸橼酸氯米酚是一种选择性雌激素受体调节剂，主要通过 CYP2D6 代谢为其 4-羟基化的活性代谢物。在这项研究中，我们研究了亚洲人群中最常见的 CYP2D6 变异等位基因 CYP2D610 对健康韩国受试者中枸橼酸氯米酚及其两种活性代谢物（4-OH-CLO 和 4-OH-DE-CLO）药代动力学的影响。22 名韩国受试者被分为三组，根据 CYP2D6 基因型，给予单次 50mg 口服枸橼酸氯米酚。CYP2D6wt/*wt（n=8；*wt=1 或 2）、CYP2D6wt/10（n=8）和 CYP2D610/10（n=6）。采用已验证的 HPLC-MS/MS 分析方法测定血浆样本中氯米酚及其代谢物的浓度，采集时间为服药后 168 小时。仅在三个 CYP2D6 基因型组之间氯米酚的 C 有显著差异（p<0.05）。矛盾的是，与其他基因型组相比，CYP2D610 纯合子携带者的两种活性代谢物的消除半衰期（t）和 AUC 均显著增加（均 p<0.001）。CYP2D610/10 受试者校正后的氯米酚活性部分 AUC 分别比 CYP2D6wt/*wt 和 *wt/*10 基因型组高 2.95 倍和 2.05 倍（均 p<0.001）。CYP2D6 遗传多态性对氯米酚及其代谢物的生物转化有一定影响，进一步研究其他 CYP 酶在多次给药条件下的作用，可为氯米酚药代动力学和/或药物反应的个体间变异性提供更明确的证据。
