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1、药物基因组学与受体阻滞剂的安全性 Pharmacogenomics and Sefaty of beta-blockers,为什么药物疗效不一样?,为什么药物疗效不一样?,药物基因组学(Pharmacogenomics),药物基因组学研究人类基因组信息与药物反应之间的关系，利用基因组学信息解答不同个体对同一药物反应上存在差异的原因。,%NON-RESPONSE TRYCYCLICS20-50%SSR inhibitors10-25%Beta-blockers15-35%ACE inhibitors10-30%5-HT1 migraine20-45%HMG Co A reductase inhi
2、b.10-30%Interferons30-70%Anti-neoplastics20-70%Beta2 adrenergic agonist40-70%,为什么药物的无效率如此之高?,为什么药物会产生不良反应?,Over 60%of the 27 drugs most frequently cited in ADRs are metabolized by at least 1 enzyme with an inherited DNA variant known to cause poor metabolism!Pharmacogenomics 2003;Lazarou et al(JAMA
3、1998),关于药酶的基因多态性,P450酶的基因多态型（Genetic polymorphism）使药物代谢存在着种族和个体差异，尤其是CYP2C19和2D6。目前分为4种表型：正常代谢型 EM,又称快代谢型（Extensive Metabolizer，占75-85%）;活性缺乏型 PM,又称慢代谢型（Poor Metabolizer,占5-10%）;超速代谢型 UM（Ultrarapid Metabolizer,占1-10%);中间代谢型 IM（Intermediate Metabolizer,占10-15%)(此型介于EM与PM之间）。,药酶基因多态性与药物浓度,(PM),(IM),(E
4、M),(UM),从基因型到表型（药酶）,Alprenolol Amitriptyline Bufuralol ClomipramineCodeine Desipramine Encainide EthylmorphineFlecainide Fluoxetine Guanoxan ImipramineMetoprolol Nortriptyline Paroxetine PhenforminPropafenone Propranolol,25%重要处方药是经2D6代谢,2D6的基因多态性,CYP2D6s的等位基因(125个;2008年)与功能正常功能:CYP2D 6*1、*2、*33、*35;
5、降低功能:CYP2D 6*9、*10、*17、*36、*41;增强功能:CYP2D 6*1N、*2N、*35N,N=*1、*2、*33、*41;(为重复序列基因多态性);全无功能:CYP2D6*3、*4、*5、*6、*7、*8、*11、*12、*13、*14、*15、*16、*18、19*、*20、*21、*38、*40、*42、*43、*44、*56、*62,2D6等位基因在不同人群中的分布,PM,UM,-受体阻滞剂在临床的重要地位涉及CVD每个环节具有不可替代的心脏保护作用,美国FDA批准应用的17个-受体阻滞剂,Pharmacotherapy.2007;27(6):874-887,-受体
6、阻滞剂应用广泛风险却很大,Blockers are among the most widely prescribed of all drug classes,with more than 120 million prescriptions in the United States in 2004;一 are recommended as a first-line agent for various diseases,including heart failure,hypertension,and angina,as well as after myocardial infarction.How
7、ever,-blocker therapy often produces variable responses among patients.Genetic differences may contribute to this variability in responses to-blockers.,肾上腺素能受体阻滞剂在心血管疾病中临床应用的专家共识中华医学会心血管病学分会和中华心血管病杂志编辑委员会(2009),不仅高度评价了受体阻滞剂的临床地位和重要作用,更重要的是强调规范使用!为什么要强调规范使用?认识上有误区;使用率低;应用不规范;选药不当.遗憾地是“共识”未提及药物基因组学对规范
8、使用受体阻滞剂的重要作用,即提高疗效、减少ADR所必需!,抗高血压的药物基因组学的过去、现在和未来Pharmacogenomics of antihypertensive drugs:past,present and future,21世纪将更加肯定高血压药物基因组学的临床价值!(The next decade should clearly define the clinical potential for hypertension pharmacogenomics.)Pharmacogenomics(2010)11(4),487491,-受体阻滞药的代谢与药酶基因多态性,大部分-受体阻滞药的
9、代谢是经CYP2D6，该酶具有遗传多态性，其基因变异可高度影响CYP2D6的活性;PM:酶活性缺乏，导致血药浓度过高,易诱发严重的不良反应,甚至死亡，临床用药应减少剂量;IM型:酶活性略微降低，此类病人用药应适当减少剂量;EM:正常人群的代谢表型，故使用推荐剂量;UM:由于多基因拷贝使酶蛋白高度表达，导致酶活性显著增高,从而使血药浓度降低而达不到治疗效果，故应适当增加剂量或改用其他药物。,美托洛尔经2D6代谢/比索洛尔则否,美托洛尔受药酶基因多态性的影响,2D6基因多态性决定-受体阻滞药的作用,Plasma metabolic ratio of metoprolol/-OH-metoprolo
10、l:PM:IM=6.2倍 PM:EM=3.9倍(P 0.01).,Pharmacogenetics 2002,12:465472,患者2D6基因多态性的分布,I,II,III,showed that normalized plasma concentration ofmetoprolol in patients homozygous for the reduced functionalallele was 3 times higher than in those with normal functional,-受体阻滞药受2D6基因多态性的影响 三组比索洛尔的谷峰浓度变化相似,-受体阻滞药受2
11、D6基因多态性的影响 美托洛尔的PK变化较大,Plasma metoprolol concentrations in poor()and extensive()metabolizers after 200 mg of metoprolol tartrate administered orally.NEJM 307:1558-1560,1982.,美托洛尔受2D6基因多态性影响显著,Fux et al.,CPT 2006,0,10,20,30,40,50,60,70,80,90,100,UM,EM,EM/het.,IM,PM,Metoprolol plasma con.(ng/ml),1.3,3
12、.9,14.2,50.8,80.5,Dose mg,100,100,100,78,74,浓度相差：60 倍,美托洛尔血药浓度与CYP2D6基因多态性的关系,Pharmacogenetics 2002,12:465472,-受体阻滞药受2D6基因多态性的影响 与心率/血压调整关系,Clinical pharmacology 85,-受体阻滞药受2D6基因多态性的影响 与心率调整关系,Clinical pharmacology 85,Atenolol,Metoprolol,美托洛尔受2D6基因多态性影响显著IM,PM患者极易中毒,美托洛尔70%经2D6代谢.,Clin Pharmacol Ther
13、 2005;78:378-87,美托洛尔在三组患者的疗效比较,2D6等位基因中国汉族的分布,The Pharmacogenomics Journal 2009:9;380394,Four major alleles of CYP2D6(*1,*2,*5 and*10)vary significantly(P0.05),美托洛尔受2D6基因多态性影响显著,Pharmacotherapy 2007;27:874887,美托洛尔等增加PM患者心动过缓的风险,leading to an increased risk of bradycardia in PM s odds ratio=3.86(95%c
14、onfidence interval 1.688.86);P=0.0014Clinical pharmacology 85,FDA推荐用前进行基因多态性检测的药品,chemical name for bisoprolol fumarate is()-1-4-2-(1-Methylethoxy)ethoxy methylphenoxy-3-(1-methylethyl)amino-2-propanol(E)-2-butenedioate,富马酸比索洛尔(Bisoprolol fumarate;康忻),最常用三种-受体阻滞剂的比较,25%,38%,1/2,120,7,75,比索洛尔的作用特点,Bi
15、soprolol has a higher degree of 1-selectivity(cardioselective)compared to other 1-selective-blockers such as atenolol,metoprolol and betaxolol,Bisoprolol has a stronger antihypertensive effect and cardioprotective;Bisoprolol inhibits renin secretion by about 65%and tachycardia by about 35%;In animal
16、 testing bisoprolol compared to propranolol has shown less sedative effects and only slightly reduced glucose tolerance.Diarrhea;dizziness;drowsiness;fatigue;headache;lightheadedness;nausea;sleeplessness;unusual tiredness;weakness.,-Blockers Differ in Their Long-Term Effects on Mortality in HF,Bisop
17、rolol1Bucindolol2Carvedilol3-5Metoprolol tartrate6Metoprolol succinate7Nebivolol8Xamoterol9,Beneficial No effectBeneficialNo effectBeneficialNo effectHarmful,1CIBIS II Investigators and Committees.Lancet.1999;353:9-13.2The BEST Investigators.N Engl J Med 2001;344:1659-1667.3Colucci WS,et al.Circulat
18、ion 1996;94:2800-2806.4Packer M,et al.N Engl J Med 2001;344:1651-1658.5The CAPRICORN Investigators.Lancet.2001;357:1385-1390.6Waagstein F,et al.Lancet.1993;342:1441-1446.7MERIT-HF Study Group.Lancet.1999;353:2001-2007.8SENIORS Study Group.Eur Heart J.2005;26:215-225.9The Xamoterol in Severe heart Fa
19、ilure Study Group.Lancet.1990;336:1-6.,比索洛尔与美托洛尔在PM患者的浓度比较稳定血浓度保证其疗效和安全,比索洛尔 n-12,比索洛尔的优良PK特征保证其最佳的性/价比,21世纪人人持有基因身份证,What is Personalized Medicine?“5R”,To the Right patient Give the Right drug At the Right timeIn the Right doseBy the Right route,21世纪努力做到个体化给药,FDA:临床医药的未来寄希望于PGx,“By 2015,we will see
20、 the beginnings of a real transformation in the therapeutics of medicine,which by 2020,will have touched virtually every disorder and the drugs that we give in 2020 will,for the most part,be those that were based on the understanding of the genome,and the things that we use today will be relegated to the dust bin.”,Thank you!,已知每一段具有专一遗传性状和功能的DNA 称为基因。一对染色体中两条染色单体上相同位置的DNA 片段，就是一对等位基因(Alleles)。等位基因可定义为“位于一对同源染色体的相同位置上，控制某一性状的、不同形态的基因”,
