Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.
Laboratoire de Biochimie et Biologie Moléculaire, CHU Nîmes-Carémeau, Nîmes, France.
Clin Pharmacol Ther. 2019 Sep;106(3):585-595. doi: 10.1002/cpt.1404. Epub 2019 Apr 10.
In addition to the effect of cytochrome P450 (CYP) 2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy and toxicity). This analysis focused on the pharmacokinetic (PK)-pharmacogenetic evaluation of tamoxifen in 730 patients with adjuvant breast cancer included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single-nucleotide polymorphisms, and comedications were obtained 6 months after treatment initiation. Plasma concentrations of endoxifen were significantly associated with CYP2D6 diplotype (P < 0.0001), CYP3A422 genotype (P = 0.0003), and concomitant intake of potent CYP2D6 inhibitors (P < 0.001). Comparison of endoxifen levels showed that the CYP2D6 phenotype classification could be improved by grouping intermediate metabolizer (IM)/IM and IM/poor metabolizer diplotype into IM phenotype for future use in tamoxifen therapy optimization. Finally, the multivariable regression analysis showed that formation of tamoxifen metabolites was independently impacted by CYP2D6 diplotype and CYP3A422, CYP2C192, and CYP2B66 genetic polymorphisms.
除细胞色素 P450（CYP）2D6 遗传多态性的影响外，他莫昔芬的代谢可能受到其他因素的影响，从而可能影响治疗效果（疗效和毒性）。本分析专注于对纳入前瞻性多中心研究的 730 例辅助乳腺癌患者进行他莫昔芬的药代动力学（PK）-药物遗传学评估。在治疗开始后 6 个月，获得了他莫昔芬和六种主要代谢物的血浆浓度、63 个单核苷酸多态性的基因型以及合并用药情况。内消旋他莫昔芬的血浆浓度与 CYP2D6 二倍型（P<0.0001）、CYP3A422 基因型（P=0.0003）和同时使用强效 CYP2D6 抑制剂显著相关（P<0.001）。对内消旋他莫昔芬水平的比较表明，对于未来的他莫昔芬治疗优化，中间代谢物（IM）/IM 和 IM/弱代谢物二倍型的中间代谢物（IM）表型分类可通过分组得到改善。最后，多变量回归分析表明，他莫昔芬代谢物的形成独立受 CYP2D6 二倍型和 CYP3A422、CYP2C192 和 CYP2B66 遗传多态性的影响。
