药物基因组学-赵用

JAMA 2001; 286: 2270-22797
不良反应与药酶变异相关最多的药物
Drug Treatment Enzyme Genotype Frequency
Fluoxetine antidepressant Imipramine antidepressant Isoniazid antituberculosis Metoprolol Beta-blocker Naproxen NSAID Phenytoin Anticonvulsant Piroxicam NSAID S-Ibuprofen NSAID S-Warfarin Anticoagulant Theophylline Brochodilator
Hyperlipidemia Depression Migraine BPHຫໍສະໝຸດ Baidu
Beta-2 agonist 40 – 75 NSAID, COX-2 20 – 50 Proton pump 20 – 90 Thiazides 50 – 75 Beta-blockers 20 – 30 ACE inhibitors 10 – 30 Angiotensin IIs 10 – 30 HMGCoA reductase inhibitors 30 – 75 SRRIs 20 – 40 Tricyclics 25 – 50 Serotonin 25 – 50 Steroid 5a-reductase 40 – 100
2D6的抑制剂
From Wikipedia, the free encyclopedia
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CYP2D6s的等位基因与功能
(2010年统计共>100个) 正常功能: CYP2D6*1、*2、*33、*35; 降低功能: CYP2D6*9、*10、*17、*36、*41; 增强功能: CYP2D6*1ⅹN、 *2ⅹN、 *35ⅹN, N= *1、*2、*33 、*41
+
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药物基因组学与药物基因学的区别
Pharmacogenetics: the study of how genetic
differences among individuals cause varied responses to a drug Pharmacogenomics: Study of the effect of variation in multiple genes, or Is the Whole Genome Application of Pharmcogenetics. 目前已将二者统一称为PGx.
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高度重视国人的2D6*10分布
2D6等位基因在人群的分布
• The prevalence of CYP2D6 poor metabolizers is approximately 6–10% in white populations, but is lower in most other ethnic groups such as Asians(2%). • while approximately 50% of Asians possess the CYP2D6*10 allele
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两类药物经酶代谢的不同结果
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β-受体阻滞剂应用广泛但风险却很大
• Blockers are among the most widely prescribed of all drug classes, with more than 120 million prescriptions in the United States in 2004; • Are recommended as a first-line agent for various diseases, including heart failure, hypertension, and angina, as well as after myocardial infarction. However, β-blocker therapy often produces variable responses among patients. Genetic differences may contribute to this variability in responses to β-blockers.
$390 million – $1.2 billion
Beta Blockers
ῲ Anti Depressants SSRIs ῲ Cholesterol Drugs Statins ῲAsthma Drugs Beta-2-agonists
$345 million – $575 million
$2.3 billion – $5.8 billion $3.8 billion – $8.8 billion
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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,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1015%)(此型介于EM与PM之间） 。
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药物无效造成财力巨大浪费
Ineffective Therapies Waste Money Major Drug
ῲ Hypertension Drugs
ACE Inhibitors ῲ Heart Failure Drugs
Cost of Ineffectiveness to Healthcare System
$560 million – $1.0 billion
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近60%药物的不良反应与基因相关
分析1991~2000年18个药物ADR报告,发现发生 率最高的27个药物中(包括Carbamazepine, fluoxetine, Ibuprofen, Imipramine, Isoniazid, Naproxen, Rifampin, Teophylline, Phenytoin, Verapamil , Warfarin等),有16个(~60%)药物的ADR发生至少与一 种药酶基因多态性(主要与poor metabolism)有关;反 之,随机抽查药物中,也有7~12%的药物与基因相关,提 示我们,如依据患者个体的基因多态性给药即可大大 减少ADR的发生!
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美托洛尔说明书明确提示
—确受到PGx的影响 Metoprolol tartrate is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of Lopressor (metoprolol tartrate) is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers.
药物基因组学与β受体阻滞剂的安全性
Pharmacogenomics and Safety of beta-blockrs
海军总医院
孙忠实 2012,5,12.北京
心血管病是全球死亡的最主要原因
WHO实况报道 —第317号2011年9月
★心血管病是全球范围造成死亡的最主要原因:与其 它任何原因相比,心血管病每年造成的死亡最多。 ★2008年估计有1730万人死于心血管病，占全球死亡的 30%;中,估计有730万死于冠心病,620万 死于中风 。 ★80%以上的心血管病死亡发生在低收入和中等收入国 家,男性和女性的发生率几乎持平。 ★到2030年,几乎有2360万人将死于心血管病,主要死于心 脏病和中风。预计它们将继续成为死亡的一个主 要原因。
©2005 Gus Rosania
CYP1A2/CYP2D6 2-6/3-10 CYP1A2/CYP2D6 12/3-10% NAT 50-59% CYP2D6 3-10% CYP2C9 2-6% CYP1A2 12% CYP1A2 12% CYP1A2 12% CYP2C9 2-6% CYP1A2 12%
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美托洛尔说明书明确提示
—确有较多的药物相互作用
Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.
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基因(组)决定药物的效应
基因组 基因 基因多态性
药物代谢酶
药物转运体
药物靶点
药物代谢动力学
药物效应动力学
药物疗效和毒性差异
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药物基因组学的优越性
―新世纪再也不是一个药包打天下了! 1,研发更有效的药物; 2,治疗开始就选用更好、更安全的药物; 3,准确的确定用药剂量; 4,早期筛查疾病; 5,生产更有效、更安全的疫苗; 6,改进药物发现及其审批过程; 7,减少总医疗费用。
Routine Use of Genetics is Coming Soon!
25%重要处方药是经2D6代谢
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2D6的底物
From Wikipedia, the free encyclopedia
三
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2D6的诱导剂
From Wikipedia, the free encyclopedia
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(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, *44,*56 , *62
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2D6等位基因在不同人群中的分布
Variant CYP2D6*2xN Phenotype UM Caucasian 1-5% Asian 0-2% African 2% Ethiopian/ Saudi 10-16%
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为什么药物疗效不一样?
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抗高血压药疗效的种族差异
*注:负值表示黑人效果更好;正值表示白人效果更好
Circulation 2008:118:1383~1393
为什么药物的无效率如此之高?
Disease Drug Class Poor/Non Responders(%)
70 – 100 25 – 50 Cancer (breast, lung, brain) Various Diabetes Sulfonylureas Asthma OA/RA Duodenal Ulcer Hypertension
From Pharmacogenomic:Social, Ethical and Clinical Dimensions, M. Rothstein, ed. 8
PGx—实现用药的Fine Tuning
个体化给药的热点:氯吡格雷(波立维)
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什么是药物基因组学?
Pharmacogenomics = drug therapy + genetic diagnostic test
CYP2D6*4
CYP2D6*10 CYP2D6*17
PM
IM IM
12-21%
1-2% 0%
1%
51% ND
2%
6% 34%
1-4%
3-9% 3-9%
CYP450 allele nomenclature committee database: http://www.imm.ki.se/cypalleles