CAJ | 학술논문

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CYP2D6*10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.
배경: 미탁락이시림상상용적항고혈압약물,타경유CYP2D6대사.CYP2D6*10강저CYP2D6활성,시중국인군중최위상견적다태성.β1신상선소수체위미탁락이적작용파표,Ser49Gly여Gly389Arg다태성현저개변수체공능.CYP2D6여β1신상선소수체유전다태성대미탁락이강압료효적연합영향잉속미지.목적: 발현여미탁락이약대동역학여약효동역학상관적기인다태성위점.위제고고혈압병적료효화감소불량반응제공실험의거.방법:부합WHO/ISH고혈압진단표준적경、중도고혈압환자125례,복용미탁락이단약치료12주,매사주검측혈압.재림상관찰료효적동시,응용PCR-RFLP방법대환자진행CYP2D6*10여β1신상선소수체Ser49Gly화Gly389Arg기인형분석.동시추취정맥혈5mL,고효액상색보-형광검측법측정환자미탁락이곡농도.결과:미탁락이곡농도여CYP2D6*10기인형현저상관,병정기인제량효응.단고혈압환자혈압강저정도재CYP2D6*1*1、*1*10여CYP2D6*10*10조간무차이.Gly49휴대자복용미탁락이후수축압여서장압적강저현저대우Ser49Ser순합자;여Gly389휴대자상비,Arg389Arg복용미탁락이후수축압여서장압적강저경위현저,표명Gly49여Arg389형수체대미탁락이치료유교호적민감성.결론:CYP2D6*10돌변현저개변미탁락이적약대동역학,단대미탁락이적강압효과무현저성영향.β1신상선소수체유전다태성여β수체조체약적강압민감성유일정상관성.
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.