Chen Yuanhuang, Marcath Lauren A, Eliassen Finn Magnus, Lende Tone Hoel, Soiland Havard, Mellgren Gunnar, Helland Thomas, Hertz Daniel Louis
Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, USA.
Department of Pharmacotherapy, Washington State University College of Pharmacy & Pharmaceutical Sciences, Spokane, WA 99202, USA.
J Pers Med. 2021 Jun 4;11(6):507. doi: 10.3390/jpm11060507.
Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with activity. Associations of tamoxifen efficacy with measured or -predicted endoxifen concentrations have been inconclusive. Another active metabolite, 4-OHtam, and other, less active metabolites, Z-4'-endoxifen and Z-4'-OHtam, have also been reported to be associated with tamoxifen efficacy.
Genotype for 20 pharmacogenes was determined by VeriDose Core Panel and VeriDose CNV Panel, followed by translation to metabolic activity phenotype following standard activity scoring. Concentrations of tamoxifen and seven metabolites were measured by UPLC-MS/MS in serum samples collected from patients receiving 20 mg tamoxifen per day. Metabolic activity was tested for association with tamoxifen and its metabolites using linear regression with adjustment for upstream metabolites to identify genes associated with each step in the tamoxifen metabolism pathway.
A total of 187 patients with genetic and tamoxifen concentration data were included in the analysis. was the primary gene associated with the tamoxifen metabolism pathway, especially the conversion of tamoxifen to endoxifen. and were also responsible for the metabolism of tamoxifen. especially impacted the hydroxylation to 4-OHtam, and this involved the OATP1B1 () transporter.
Multiple genes are involved in tamoxifen metabolism and multi-gene panels could be useful to predict active metabolite concentrations and guide tamoxifen dosing.
他莫昔芬作为雌激素受体阳性（ER+）乳腺癌的一种治疗药物，是一种弱抗雌激素药物，需要代谢激活才能形成具有更高抗雌激素活性的代谢物。4-羟基他莫昔芬是研究最多的活性他莫昔芬代谢物，其浓度与活性高度相关。他莫昔芬疗效与测得的或预测的4-羟基他莫昔芬浓度之间的关联尚无定论。另一种活性代谢物4-OHtam，以及其他活性较低的代谢物Z-4'-羟基他莫昔芬和Z-4'-OHtam，也被报道与他莫昔芬疗效相关。
通过VeriDose核心面板和VeriDose CNV面板确定20个药物基因的基因型，然后按照标准活性评分转化为代谢活性表型。采用超高效液相色谱-串联质谱法（UPLC-MS/MS）测定从每天接受20mg他莫昔芬治疗的患者采集的血清样本中他莫昔芬及其七种代谢物的浓度。使用线性回归并对上游代谢物进行校正，测试代谢活性与他莫昔芬及其代谢物之间的关联，以确定与他莫昔芬代谢途径中每个步骤相关的基因。
共有187例具有基因和他莫昔芬浓度数据的患者纳入分析。是与他莫昔芬代谢途径相关的主要基因，尤其是他莫昔芬向4-羟基他莫昔芬的转化。和也参与他莫昔芬的代谢。尤其影响向4-OHtam的羟基化，这涉及有机阴离子转运多肽1B1（）转运体。
多个基因参与他莫昔芬代谢，多基因面板可能有助于预测活性代谢物浓度并指导他莫昔芬给药。
