南方医科大学学报

南方医科大学学报 ›› 2019, Vol. 39 ›› Issue (03): 328-.doi: 10.12122/j.issn.1673-4254.2019.03.11

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CYP2D6*10 对冠心病患者美托洛尔谷浓度和血压心率的影响

朱茜，赖伟华，黎励文，李汉平，钟诗龙   

  • 出版日期:2019-03-20 发布日期:2019-03-20

Effects of CYP2D6*10 on plasma trough concentration of metoprolol in patients with coronary artery disease

  • Online:2019-03-20 Published:2019-03-20

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摘要： 目的探讨CYP2D6 *10（c.100 C>T）对冠心病患者血浆中美托洛尔及代谢物α-羟化美托洛尔谷浓度和血压心率的影响。 方法将患者分成服用美托洛尔片（n=128）和美托洛尔缓释片（n=126）两组，用Taqman 实时荧光定量PCR对CYP2D6*10进行 基因分型，UPLC-MS/MS测定美托洛尔和α-羟化美托洛尔的谷浓度，分别比较两组患者中不同CYP2D6*10基因型患者的美托 洛尔和α-羟化美托洛尔的剂量校正浓度（C/D）的差异。记录患者美托洛尔达稳态时的静息血压和心率，比较两组患者中不同基 因型患者之间血压和心率的差异。结果服用美托洛尔缓释片的患者中，α-羟化美托洛尔谷浓度与收缩压相关（P=0.0204）。 CYP2D6*10慢代谢型对两组患者的美托洛尔和α-羟化美托洛尔浓度均有显著影响（P<0.01），两组患者中TT型较CC型和CT 型患者美托洛尔C/D高（均P<0.01）；与CT型相比，TT型患者α-羟化美托洛尔C/D较低（P<0.01）。服用美托洛尔缓释片的患者 中，与CC型相比，CT型（P=0.0281）和TT型（P=0.0196）患者舒张压较低，而两组患者中不同基因型患者之间收缩压和心率均无 统计学差异。结论CYP2D6*10T等位基因突变可使冠心病患者美托洛尔代谢减慢，血浆中美托洛尔浓度增加而α-羟化美托洛 尔浓度和舒张压降低，CYP2D6*10对患者美托洛尔达稳态时的静息收缩压和心率无显著影响。

Abstract: Objective To study the effect of CYP2D6*10 (c.100 C>T) on plasma trough concentrations of metoprolol and its metabolite α- hydroxy metoprolol, blood pressure and heart rate in patients with coronary artery disease. Methods The patients with coronary artery disease taking metoprolol tablets (n=128) and those taking metoprolol sustained-release tablets (n=126) were genotyped for CYP2D6*10 using Taqman real- time quantitative PCR. The trough concentrations of metoprolol and α-hydroxy metoprolol were determined with UPLC-MS/MS, and the dose-normalized concentrations (C/D) were compared among the patients with different CYP2D6*10 genotypes in both groups. Resting blood pressure and heart rate were recorded in all the patients when the concentration of metoprolol reached the steady state and were compared among the patients with different genotypes. Results In patients taking metoprolol sustained-release tablets, the plasma trough concentration of α-hydroxy metoprolol was significantly associated with the systolic blood pressure (P=0.0204). The CYP2D6* 10 poor metabolizers showed a significant association with the C/D of metoprolol and α-hydroxy metoprolol (P<0.01) in patients receiving metoprolol in both formulations, and in both groups, the C/D of metoprolol was significantly higher in the patients with a TT genotype than in those with a CC or CT genotype (P<0.01); compared with those with the CT genotype, the patients with the TT genotype had a significantly lower C/D of α-hydroxy metoprolol (P<0.01). In patients taking metoprolol sustained-release tablets, those with the CT (P=0.0281) and TT (P=0.0196) genotypes had lower diastolic blood pressure than patients with the CC genotypes, but the systolic blood pressure or heart rate did not differ significantly among them. Conclusion CYP2D6*10T allele mutation can reduce the metabolism of metoprolol, increase the C/D of metoprolol and decrease the C/D of α-metoprolol and diastolic blood pressure in patients with coronary artery disease, but CYP2D6*10 variation does not significantly affect systolic blood pressure or heart rate in the patients when the concentration of metoprolol reaches a steady state.