β1肾上腺素受体与CYP2D6基因多态性对美托洛尔抗高血压治疗的药代动力学和药效学影响

背景：美托洛尔是临床常用的抗高血压药物,它经由CYP2D6代谢。CYP2D6＊10降低CYP2D6活性,是中国人群中最为常见的多态性。β1肾上腺素受体为美托洛尔的作用靶标,Ser49Gly与Gly389Arg多态性显著改变受体功能。CYP2D6与β1肾上腺素受体遗传多态性对美托洛尔降压疗效的联合影响仍属未知。目的：发现与美托洛尔药代动力学与药效动力学相关的基因多态性位点。为提高高血压病的疗效和减少不良反应提供实验依据。方法：符合WHO/ISH高血压诊断标准的轻、中度高血压患者125例,服用美托洛尔单药治疗12周,每四周检测血压。在临床观察疗效的同时,应用PCR-RFLP方法对患者进行CYP2D6＊10与β1肾上腺素受体Ser49Gly和Gly389Arg基因型分析。同时抽取静脉血5mL,高效液相色谱-荧光检测法测定患者美托洛尔谷浓度。结果：美托洛尔谷浓度与CYP2D610基因型显著相关,并呈基因剂量效应。但高血压患者血压降低程度在CYP2D6＊1＊1、1＊10与CYP2D6＊10＊10组间无差异。Gly49携带者服用美托洛尔后收缩压与舒张压的降低显著大于Ser49Ser纯合子;与Gly389携带者相比,Arg389Arg服用美托洛尔后收缩压与舒张压的降低更为显著,表明Gly49与Arg389型受体对美托洛尔治疗有较好的敏感性。结论：CYP2D6＊10突变显著改变美托洛尔的药代动力学,但对美托洛尔的降压效果无显著性影响。β1肾上腺素受体遗传多态性与β受体阻滞药的降压敏感性有一定相关性。

Effects of β1-adrenergic receptor and CYP2D6 genetic polymorphism on metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy

BACKGROUND: Metoprolol is a selective β1-Blocker commonly used in essential hypertension. It is metabolized by CYP2D6. CYP2D6*10, which was identified to decrease activity of CYP2D6, is the main variance in Chinese population. β1-adrenergic receptor, with Ser49Gly and Gly389Arg polymorphisms, is the target of metoprolol. It was still unknown that whether the CYP2D6 and β1-adrenergic receptor had a synergic effect on metoprolol antihypertension therapy. AIM: To clarify the genetic polymorphism associated with metoprolol pharmacokinetics and pharmacodynamics in antihypertension therapy. METHODS: 125 mild-to-med essential hypertension patients were enrolled in this study. Patients were mono-therapied with metoprolol for 12 weeks. Blood pressure was monitored every 4 weeks. PCR-RFLP method was use to identify CYP2D6*10 and β1-adrenergic receptor Ser49Gly and Gly389Arg polymorphisms. Plasma metoprolol concentration was measured by HPLC- fluorescence detection. RESULTS: Trough blood level (C0) of metoprolol was associated with CYP2D6*10 variance in a gene-dose-effect manner, whereas the extent of blood pressure decrease was not significant different in CYP2D6*1*1, *1*10 and CYP2D6*10*10 patients. After 12 weeks metoprolol therapy, Gly49 carriers had stronger decrease in systolic and diastolic blood pressure than that of Ser49 homozygotes. Similarly, subjects homozygous for Arg389 had stronger decrease in blood pressure than that of Gly389 carriers. CONCLUSION: CYP2D6*10 variance significantly change the pharmacokinetics of metoprolol, and the genetic polymorphisms of β1-adrenergic receptor were associated with the pharmacodynamics of metopolol in antihypertension therapy.