Department of Genomic Medicine, African Institute of Biomedical Science and Technology (AiBST), Beatrice, Zimbabwe.
Department of Biotechnology, Chinhoyi University of Technology, Chinhoyi, Zimbabwe.
Br J Clin Pharmacol. 2023 Oct;89(10):3209-3216. doi: 10.1111/bcp.15827. Epub 2023 Jun 26.
Tamoxifen is the most used hormonal therapy for oestrogen receptor-positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC-MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/mL, and in 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold of 5.97 ng/mL. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (P = 0.0151) and with endoxifen to N-desmethyl-tamoxifen ratios (P = 0.0006).
他莫昔芬是治疗雌激素受体阳性乳腺癌最常用的激素治疗药物。CYP2D6 是他莫昔芬向终末昔芬代谢途径中的主要酶。终末昔芬血浆浓度的变化与 CYP2D6 多态性有关。本研究旨在确定津巴布韦乳腺癌患者队列（n=40）中 CYP2D6 多态性与终末昔芬血浆浓度之间的关系。采用 TaqMan 基因分型和拷贝数测定法确定 CYP2D6 基因型。采用 LC-MS/MS 定量测定他莫昔芬及其代谢物。该人群 CYP2D6 功能降低等位基因17（15%）和29（18%）的频率较高。终末昔芬的中位数浓度为 4.78ng/mL，在 55%的患者中，大多数中间代谢物低于 5.97ng/mL 的终末昔芬治疗阈值。CYP2D6 表型和活性评分与终末昔芬血浆浓度（P=0.0151）和终末昔芬与 N-去甲基他莫昔芬比值（P=0.0006）显著相关。
