摘要
目的：检测中国贵州地区汉族心衰患者中MDR1C3435T、CYP3A4*18B和CYP3A5*3等位基因突变率,观察MDR1C3435T、CYP3A4*18B和CYP3A5*3基因多态性对地高辛血药浓度的影响。为以基因多态性为导向的地高辛合理用药和个体化用药提供重要的理论依据。
方法：收集了111名中国贵州地区汉族心衰患者的治疗药物浓度监测(Therapeutic Drug Monitorng,TDM)数据,及每个患者的人口学、肝肾功能、血常规、合并用药等信息资料。将这些患者测定地高辛血药浓度后的废弃血收集保存,提取血样DNA,并通过聚合酶链反应-限制性片段长度多态性(Polymerase chain reaction-Restriction fragment length polymorphism,PCR-RFLP)法分析患者的MDR1C3435T、CYP3A5*3及CYP3A4*18B基因型。对以上收集及实验获得的数据进行考察,将患者按基因型分为野生型纯合子、突变型杂合子和突变型纯合子三组,分析每个基因的多态性对地高辛血药浓度的影响。
结果：(1)111例中国汉族患者,地高辛口服剂量为0.125mg,Qd；血药浓度检测值为1.06±0.72ng/mL；(2)MDR1C3435T、CYP3A4*18B和CYP3A5*3等位基因在中国汉族心衰患者中的突变率分别为39.60%、30.60%和66.70%。等位基因和基因型分布符合Hardy-Weinberg平衡；(3)比较MDR1各基因型组的地高辛血药浓度后发现：野生纯合子(CC)组、突变杂合子(CT)组、突变纯合子(TT)组的地高辛血药浓度依次为0.89±0.55ng/mL、1.08±0.73ng/mL、1.37±0.95ng/mL。CC组与TT组的地高辛血药浓度差异有统计学意义(P<0.05)；(4)CYP3A4和CYP3A5各基因型组之间的地高辛血药浓度差异均无统计学意义(P>0.05)。
结论：(1)MDR1C3435T等位基因突变可使地高辛血药浓度提高；(2)CYP3A4*18B和CYP3A5*3等位基因突变对地高辛的血药浓度无明显影响。
Objective:to determine the frequencies of MDR1C3435T, CYP3A4*18B and CYP3A5*3 in Chinese Han patients with chronic heart failure and to observe the impact of MDR1C3435T, CYP3A4*18B and CYP3A5*3 genetic polymorphism on serum digoxin concentration. This study provides an important theoretical evidence for the gene-directed rationalization and individualization of medication for digoxin.
Methods:A group of 111 unrelated Chinese Han patients with chronic heart failure were recruited after them taken therapeutic drug monitoring (TDM). Demographic data, blood, liver and kidney function data and drug combination data were retrospectively collected. In addition, genotyping of MDR1C3435T, CYP3A4*18B and CYP3A5*3 alleles were conducted by PCR-RFLP method. We investigated above data and analyzed the effect of MDR1C3435T, CYP3A4*18B and CYP3A5*3 genetic polymorphism on serum digoxin concentration.
Results:(1) The dosage of digoxin for 111 Chinese Han patients is 0.125mg, Qd; and the mean of serum digoxin concentration is 1.06±0.72ng/mL; (2)The frequencies of MDR1C3435T, CYP3A4*18B and CYP3A5*3 in Chinese Han patients of Guizhou were 39.60％、30.60% and 66.70%, respectively. The allelic frequency was consistent with Hardy-Weinberg equilibrium; (3)The serum digoxin concentration in MDR1CC3435 and MDR1TT3435 groups showed a significant difference, with a mean TDM value 0.89+0.55 ng/mL versus 1.37±0.95 ng/mL (P<0.05); (4)There were no statistical difference on the serum digoxin concentration with CYP3A4*18B or CYP3A5*3 genetic polymorphism (P>0.05).
Conclusions:(1) The effect of MDR1C3435Tgenetic polymorphism increased the serum digoxin concentration; (2) CYP3A4*18B or CYP3A5*3 genetic polymorphism may have no significant effect on the serum digoxin concentration.
引文
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