Lim Joanne Siok Liu, Sutiman Natalia, Muerdter Thomas E, Singh Onkar, Cheung Yin Bun, Ng Raymond Chee Hui, Yap Yoon Sim, Wong Nan Soon, Ang Peter Cher Siang, Dent Rebecca, Schroth Werner, Schwab Matthias, Chowbay Balram
Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
Clinical Pharmacology, SingHealth, Singapore.
Br J Clin Pharmacol. 2016 Jun;81(6):1142-52. doi: 10.1111/bcp.12886. Epub 2016 Mar 8.
The aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer.
Sixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C192, CYP2C193 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Steady-state concentrations of tamoxifen and its metabolites were quantified using liquid chromatography–mass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypic–phenotypic associations and haplotypic effects of the SNPs.
CYP2C19 functional polymorphisms and their linked SNPs were not significantly associated with plasma concentrations of tamoxifen and its main metabolites N-desmethyltamoxifen, (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. However, CYP2C192 and its seven linked SNPs were significantly associated with lower NorEND concentrations, MRNorEND/NDDM and MRNorEND/(Z)-END. Specifically, patients carrying the CYP2C192 variant allele A had significantly lower NorEND concentrations [median (range), GG vs. GA vs. AA: 1.51 (0.38–3.28) vs. 1.28 (0.30–3.36) vs. 1.15 ng ml−1 (0.26–2.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA: 9.40 (3.27–28.35) vs. 8.15 (2.67–18.9) vs. 6.06 (4.47–14.6), P < 0.0001] and MRNorEND/NDDM [GG vs. GA vs. AA: 2.75 (0.62–6.26) vs. 2.43 (0.96–4.18) vs. 1.75 (1.10–2.49), P < 0.00001]. CYP2C19 H2 haplotype, which included CYP2C19*2, was also significantly associated with lower NorEND concentrations (P = 0.0020), MRNorEND/NDDM (P < 0.0001) and MRNorEND/(Z)-END (P < 0.0001), indicating significantly lower formation rates of NorEND.
These data highlight the potential relevance of CYP2C19 pharmacogenetics in influencing NorEND concentrations in tamoxifen-treated patients, which may influence treatment outcomes.
本研究旨在探讨CYP2C19基因变异及其相关单倍型对亚洲乳腺癌患者中他莫昔芬及其代谢产物，尤其是去甲恩杂鲁胺（NorEND）处置的影响。
在240名健康亚洲人中鉴定出66个CYP2C19多态性位点，其中14个被发现与CYP2C192、CYP2C193和CYP2C19*17紧密连锁。在接受他莫昔芬治疗的201名亚洲乳腺癌患者中对这17个单核苷酸多态性（SNP）进行了进一步基因分型。采用液相色谱 - 质谱法定量他莫昔芬及其代谢产物的稳态浓度。运用非参数检验和回归方法评估SNP的基因型 - 表型关联和单倍型效应。
CYP2C19功能多态性及其连锁的SNP与他莫昔芬及其主要代谢产物N - 去甲基他莫昔芬、（Z）-4 - 羟基他莫昔芬和（Z）-恩杂鲁胺的血浆浓度无显著关联。然而，CYP2C192及其7个连锁的SNP与较低的NorEND浓度、MRNorEND/NDDM和MRNorEND/（Z）-END显著相关。具体而言，携带CYP2C192变异等位基因A的患者NorEND浓度显著较低[中位数（范围），GG与GA与AA：1.51（0.38 - 3.28）对1.28（0.30 - 3.36）对1.15 ng/ml（0.26 - 2.45，P = 0.010）]，以及MRNorEND/（Z）-END显著较低[GG与GA与AA：9.40（3.27 - 28.35）对8.15（2.67 - 18.9）对6.06（4.47 - 14.6），P < 0.0001]和MRNorEND/NDDM[GG与GA与AA：2.75（0.62 - 6.26）对2.43（0.96 - 4.18）对1.75（1.10 - 2.49），P < 0.00001]。包含CYP2C19*2的CYP2C19 H2单倍型也与较低的NorEND浓度（P = 0.0020）、MRNorEND/NDDM（P < 0.0001）和MRNorEND/（Z）-END（P < 0.0001）显著相关，表明NorEND的生成率显著降低。
这些数据凸显了CYP2C19药物遗传学在影响他莫昔芬治疗患者NorEND浓度方面的潜在相关性，这可能会影响治疗结果。
