CYP2C19基因多态性及患者主要临床资料与氯吡格雷药物抵抗的相关性研究

目的观察药物代谢酶系统中CYP2C19基因多态性及患者主要临床资料与服用氯吡格雷前后血小板聚集率变化(氯吡格雷药物抵抗)的相关性。方法入选拟行冠脉造影检查或支架植入治疗患者35例,根据围手术期应用氯吡格雷前后血小板聚集率变化,将患者分为氯吡格雷抵抗组和非抵抗组。检测CYP2C19基因型,并记录患者年龄、性别、烟酒史、高血压、糖尿病等主要临床资料,分析基因水平及临床水平各因素对血小板聚集及氯吡格雷药物抵抗的影响。结果检测出氯吡格雷抵抗的患者15例,CYP2C19慢代谢基因型患者4例,Logistic回归分析显示,CYP2C19基因型是氯吡格雷抵抗的危险因素(OR=1.236,95%CI:0.273~5.599,P=0.049)。结论 CYP2C19基因型在基因水平与氯吡格雷抵抗相关,临床水平资料未见明显相关性。     

细胞色素P450 3A5基因多态性与氯吡格雷抵抗的相关性研究

目的探讨脑梗死患者中细胞色素P450 3A5(CYP3A5)基因多态性与氯吡格雷抵抗的相关性。方法将200例脑梗死患者按服药后的血小板聚集率分为氯吡格雷抵抗(CR)组72例和非氯吡格雷抵抗(NCR)组128例。2组患者均予以氯吡格雷75 mg,qd,口服+阿司匹林100 mg,qd,口服。用基因芯片法检测CYP3A5 6989基因型与等位基因分布,比较2组患者的血小板聚集率和血栓发生率,并对CYP3A5 6989与氯吡格雷抵抗之间的相关性进行分析。结果治疗后,CR组和NCR组的血小板聚集率分别为(58.31±14.73)%和(88.45±20.45)%,血栓发生率分别为16.67%(12例/72例)和0.78%(1例/128例),CYP3A5 6989中AA型分布频率分别为48.62%和7.03%,CYP3A56989中GG型分布频率分别为19.44%和58.59%,差异均有统计学意义(均P<0.05)。CR组和NCR组的A等位基因分别为64.58%和24.22%,G等位基因分别为35.42%和75.78%,差异均有统计学意义(均P<0.05)。结论在脑梗死患者中,CYP3A5基因多态性与氯吡格雷抵抗间存在着显著的相关性。     

质子泵抑制剂与他汀类药物对氯吡格雷作用的影响

目的：探讨质子泵抑制剂（PPI）与他汀类药物对氯吡格雷作用的影响。方法：查阅国内外文献,综述氯吡格雷与PPI或他汀类药物之间相互作用的情况。结果：PPI和部分他汀类药物对氯吡格雷的影响体现在代谢过程中对CYP2C19和CYP3A4的竞争和抑制,以及CYP450的基因多态性上。同时服用此3类药物的患者抗血小板作用可能无法达到预期效果。结论：就氯吡格雷、PPI和他汀类药物三者之间相互作用而言,建议错时服用或选用对氯吡格雷影响较小的药物。     

对氯吡格雷不同反应的冠状动脉疾病患者基因型差异研究

目的:探讨对氯吡格雷不同反应的冠状动脉疾病(CAD)患者基因型的差异。方法:选取2013年3月-2015年11月于我院心内科就诊的CAD患者159例,予氯吡格雷+阿司匹林双联抗血小板治疗至少1年。采用光比浊法测定各患者治疗前后经腺苷二磷酸(ADP)、花生四烯酸(AA)诱导的血小板聚集百分率,采用聚合酶链反应-限制性片段长度多态性分析法检测其细胞色素P450(CYP)2C19、CYP3A5、野生型亮氨酸33等位基因(PLA1)/脯氨酸33等位基因(PLA2)的多态性。结果:共检出CYP2C19基因型3种(*2/*2、*2/*1、*1/*1)、CYP3A5基因型3种(*3/*3、*3/*1、*1/*1)、PLA1/PLA2基因型3种(A1/A2、A2/A2、A1/A1),各基因型频率均符合Hardy-Weinberg平衡(P>0.05)。159例患者中,有81例为氯吡格雷"半反应",占50.9%;有78例为氯吡格雷"反应",占49.1%。氯吡格雷"半反应"患者CYP2C19基因缺失(*2/*2或*2/*1基因型)和*2等位基因的频率均显著高于氯吡格雷"反应"患者,差异均有统计学意义(P<0.05);氯吡格雷"半反应"患者PLA1/PLA2基因缺失(A2/A2或A1/A2基因型)和A2等位基因的频率均显著高于氯吡格雷"反应"患者,差异均有统计学意义(P<0.05);而氯吡格雷"半反应"患者CYP3A5基因缺失(*3/*3或*3/*1基因型)和*3等位基因的频率虽略高于氯吡格雷"反应"患者,但差异均无统计学意义(P>0.05)。治疗后,各基因型患者经ADP、AA诱导的血小板聚集百分率均较治疗前显著降低,但CYP2C19基因缺失型、CYP3A5基因缺失型患者的血小板聚集百分率均显著高于其基因表达型(*1/*1基因型),差异均有统计学意义(P<0.05);PLA1/PLA2基因缺失型与其基因表达型(A1/A1基因型)患者的血小板聚集百分率比较,差异无统计学意义(P>0.05)。结论:氯吡格雷"半反应"在CAD患者中的发生率较高。CYP2C19、PLA1/PLA2基因多态性可能与氯吡格雷"半反应"有关,而CYP3A5基因多态性可能与之无关。CYP2C19、CYP3A5基因缺失可能会降低氯吡格雷对CAD患者血小板聚集的抑制作用。     

基因多态性对氯吡格雷药理作用和临床反应的影响

氯毗格雷是治疗急性冠脉综合征的重要药物之一,然而部分患者未从氯吡格雷抗血小板治疗中获益。氯吡格雷是一种前体药物,需要经多种CYP450酶转化为活性代谢物。多项研究表明CYP2C19基因变异是影响氯吡格雷反应的重要因素。CYP2C19变异等位基因（＊2或＊3等位基因）携带者体内活性代谢物浓度下降,血小板活化的抑制作用减弱和不良心血管事件增加。P-糖蛋白变异引起氯吡格雷生物利用度下降。其他参与氯吡格雷代谢的CYP450酶多态性对人体氯吡格雷的药理作用的影响结果不一致。     

细胞色素P450基因多态性对心血管药物疗效的影响

目的探讨细胞色素P450酶2C19基因(CYP2C19)681G/A多态性对氯吡格雷治疗冠状动脉粥样硬化性心脏病(CAHD)的影响。方法选取佛山市南海区第二人民医院心内科CADH患者274例,其中130例口服氯吡格雷,选取佛山市111例调查的自然人群为对照组,口服氯吡格雷患者中52例进行了择期经皮冠状动脉介入术(PCI)治疗,比较氯吡格雷治疗后患者各基因型与实验室氯吡格雷抵抗之间的关系,并分别比较不同基因型组间血小板聚集率、实验室氯吡格雷抵抗和不良心血管事件的再发生情况。结果氯吡格雷治疗后CYP2C19681AA型平均血小板聚集率降低幅度最小,GA型次之,GG型最高;PCI患者CYP2C19681A等位基因携带者组不良心血管事件再发率高、平均血小板聚集率降低幅度小、实验室氯吡格雷抵抗发生率高。结论 CYP2C19681G/A突变是CAHD患者口服氯吡格雷治疗疗效及预后欠佳的主要影响因素,它减弱了氯吡格雷对血小板的抑制作用。     

ABCB1基因多态性与甲基化对氯吡格雷和阿司匹林抵抗影响的研究进展

氯吡格雷联合阿司匹林的双重抗血小板治疗是预防介入术后缺血事件再发生的标准药物治疗方案。然而仍有部分患者会出现氯吡格雷抵抗和阿司匹林抵抗现象。两种药物产生抵抗存在很多方面的影响因素,如患者的依从性、给药剂量、遗传因素等。遗传因素为主要因素,相关研究较多。目前,已经发布了CYP2C19基因多态性的药物剂量调整指南,但ABCB1基因对两种药物抵抗影响的研究并未达成一致的结论。本文对ABCB1基因多态性与甲基化对氯吡格雷抵抗和阿司匹林抵抗的影响进行综述,主要包括:氯吡格雷和阿司匹林抵抗的概念,ABCB1基因多态性与两药抵抗相关性,ABCB1基因启动子区域甲基化差异对药物抵抗的影响等。     

他汀类药物对氯吡格雷抗血小板作用影响的Meta分析

目的系统地评价经CYP3A4代谢和经非CYP3A4代谢的他汀类药物对氯吡格雷抗血小板作用的影响。方法计算机检索Cochrane Library、Pub Med、Web of Science、Eslsevier、CNKI、VIP、CBM、万方数据库、万方医学网,对纳入的文献进行质量评价与数据提取后,用R3.0.3软件对数据进行合并分析。结果经CYP3A4代谢和经非CYP3A4代谢的他汀类药物与氯吡格雷联用对最大血小板聚集率和主要不良心脑血管事件的影响组间均无显著差异,分别为[SMD=0.07,95%,CI(-0.03,0.17),P=0.17]和[OR=1.04,95%,CI(0.78,1.40),P=0.77];40 mg阿托伐他汀会抑制氯吡格雷的抗血小板作用[SMD=-0.33,95%,CI(-0.65,-0.01),P=0.03];经CYP3A4代谢的他汀类药物会显著降低氯吡格雷抑制血小板颗粒膜糖蛋白(CD62P)表达的作用[SMD=-0.21,95%,CI(-0.35,-0.06),P=0.005]。结论经不同途径代谢的他汀类药物与氯吡格雷联用引起MACCE无差异;40 mg阿托伐他汀会抑制氯吡格雷的抗血小板作用;首次发现经CYP3A4代谢的他汀类药物会降低氯吡格雷对CD62P表达的抑制作用。     

我国北方汉族冠心病人群氯吡格雷抵抗相关影响因素的回顾研究

目的:探讨影响我国北方汉族冠心病人群氯吡格雷抵抗的相关影响因素。方法:选择425例首次行经皮冠状动脉介入术的患者,根据血小板聚集率结果将患者分为氯吡格雷抵抗(CRG)组和氯吡格雷敏感(CSG)组。检测其基因型,分析其CYP2C19*2等位基因携带状态,并分析血小板聚集率等实验室指标和冠心病易感指标等与其是否发生氯吡格雷抵抗的相关性。结果:CYP2C19基因G681A突变携带者(GA、AA)在CRG组与CSG组的分布率分别为64.4%和33.1%,携带突变基因与否在两组间的分布比较差异具有统计学意义(P<0.000 1),而其他非遗传性指标在两组间比较差异无统计学意义(P>0.05)。结论:CYP2C19*2等位基因的携带与氯吡格雷抵抗有显著的相关性,G681A突变基因的携带是导致氯吡格雷抵抗的危险因素,其他非遗传因素与氯吡格雷抵抗的关联不大。     

氯吡格雷抵抗及其对策

氯吡格雷在急性冠脉综合征和经皮冠状动脉介入治疗前后发挥重要作用。氯吡格雷是血小板膜上P2Y_(12)受体的拮抗药。氯吡格雷抵抗包括对氯吡格雷无反应和对氯吡格雷低反应。氯吡格雷抵抗者血小板聚集率高,易发生心血管事件。本文对氯吡格雷的作用机制、氯吡格雷抵抗原因及治疗对策等作一综述。     

The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin.

The prodrug clopidogrel (Plavix) is activated by cytochrome p450 (p450) to a metabolite that inhibits ADP-induced platelet aggregation. Clopidogrel is frequently administered to patients in conjunction with the CYP3A4 substrate atorvastatin (Lipitor). Since clinical studies indicate that atorvastatin inhibits the antiplatelet activity of clopidogrel, we investigated whether CYP3A4 metabolized clopidogrel in vitro. Microsomes prepared from dexamethasone-pretreated rats metabolized clopidogrel at a rate of 3.8 nmol min(-1) nmol of p450(-1), which is 65 and 1270% faster than the rate of metabolism by microsomes from control and beta-napthoflavone-treated rats, respectively. To identify the human p450s responsible for clopidogrel oxidation, genetically engineered microsomes containing a single human p450 isozyme were tested for their ability to oxidize clopidogrel. CYP3A4 and 3A5 metabolized clopidogrel at a significantly higher rate than eight other p450 isozymes, suggesting that CYP3A4 and 3A5 are primarily responsible for in vivo clopidogrel metabolism. Clopidogrel interacts with human CYP3A4 with a spectral dissociation constant (K(s)), K(m), and V(max) of 12 microM, 14 +/- 1 microM and 6.7 +/- 1 nmol min(-1) nmol p450(-1), respectively. Atorvastatin lactone, the physiologically relevant substrate, inhibits clopidogrel with a K(i) of 6 microM. When clopidogrel and atorvastatin are present at equimolar concentrations, clopidogrel metabolism is inhibited by greater than 90%. Since CYP3A4 and 3A5 metabolize clopidogrel faster than other human p450 isozymes and are the most abundant p450s in human liver, they are predicted to be predominantly responsible for the activation of clopidogrel in vivo.     

Thienopyridines and statins: assessing a potential drug-drug interaction

Clopidogrel and statins are frequently administered in patients with ischemic heart disease or other atherothrombotic manifestations and are effective in the prevention of cardiovascular disease. The thienopyridine clopidogrel is a pro-drug metabolised in the liver via the cytochrome P450 (CYP) 3A4 system to the active compound which inhibits the P2Y(12) ADP platelet receptor. The assumption exists that the effect of clopidogrel in inhibiting platelet aggregation is attenuated by co-administration of lipophilic statins such as atorvastatin or simvastatin which are metabolised by the CYP3A4 system to inactive substrates. Assessing a possible drug-drug interaction ex-vivo, inconclusive studies have been published: In an aggregometer study, a strong and dose-dependent interference between atorvastatin and the inhibitory effect of clopidogrel on platelet function was observed. Another study, measuring the effect of clopidogrel by flow cytometry, found a significant attenuation of the clopidogrel effect by lipophilic statins, predominantly in the loading phase. In contrast a recent study, which used 600 mg clopidogrel for loading, found no significant interference between various statins and clopidogrel on ADP-induced platelet aggregation and in addition another study revealed no attenuation of the clopidogrel effect despite statin co-medication after 5 weeks. Additionally, retrospective analysis of clinical studies (CREDO-study) or registries (MITRA-PLUS) revealed no significant influence of different statins on the clinical outcome in patients treated with clopidogrel. However, these clinical studies showed a trend towards a diminishing effect of clopidogrel on those treated with cytochrome CYP3A4 metabolised statins. Even more important seems to be the considerable variability in the response of the antiplatelet effect of clopidogrel. A certain percentage of patients apparently do not respond adequately to clopidogrel treatment. This effect of clopidogrel resistance seems to be more important as the potential interference between CYP3A4 metabolized statins and clopidogrel. Finally, up until now sufficient evidence has not been gained to prefer hydrophil statins on patients receiving clopidogrel co-medication or when to discontinue the use of statins in clopidogrel treatment. Prospective studies are necessary in order to evaluate the magnitude of clopidogrel resistance and the impact of clopidogrel co-medication as well as to redefine antithrombotic therapy for this subgroup.     

皖南地区CYP2C19基因多态性对PCI术后氯吡格雷抗血小板聚集的影响

目的：研究皖南地区CYP2C19基因型分布及其多态性对PCI术后患者氯吡格雷临床疗效的影响。方法：选取我院2017年7月至2017年10月行冠脉造影检查和PCI术治疗的患者100例,采用荧光染色原位杂交技术检测CYP2C19基因型,采用TEG血栓弹力图仪检测血小板聚集抑制率,比较CYP2C19不同基因型及相关指标对血小板聚集抑制率、氯吡格雷抵抗的影响。结果及结论：结果表明,CYP2C19弱代谢型是氯吡格雷抵抗的独立危险因素。氯吡格雷抵抗与CYP2C19弱代谢型相关。     

Impact of genetic polymorphisms and drug-drug interactions on clopidogrel and prasugrel response variability

Thienopyridine antiaggregating platelet agents (clopidogrel and prasugrel) act as irreversible P2Y12 receptor inhibitors. They are used with aspirin to prevent thrombotic complications after an acute coronary syndrome or percutaneous coronary intervention. A large interindividual variability in response to clopidogrel and to a lesser extent to prasugrel is observed and may be related to their metabolism. Clopidogrel and prasugrel are indeed prodrugs converted into their respective active metabolites by several cytochromes P450 (CYPs). Besides clopidogrel inactivation (85%) by esterases to the carboxylic acid, clopidogrel is metabolized by CYPs to 2-oxo-clopidogrel (15%) and further metabolized to an unstable but potent platelet-aggregating inhibitor. Prasugrel is more potent than clopidogrel with a better bioavailability and lower pharmacodynamic variability. Prasugrel is completely converted by esterases to an intermediate oxo-metabolite (R-95913) further bioactivated by CYPs. Numerous clinical studies have shown the influence of CYP2C19 polymorphism on clopidogrel antiplatelet activity. Moreover, unwanted drug-drug pharmacokinetic interactions influencing CYP2C19 activity and clopidogrel bioactivation such as with proton pump inhibitors remain a matter of intense controversy. Several studies have also demonstrated that CYP3A4/5 and CYP1A2 are important in clopidogrel bioactivation and should also be considered as potential targets for unwanted drug-drug interactions. Prasugrel bioactivation is mainly related to CYP3A4 and 2B6 activity and therefore the question of the effect of drug-drug interaction on its activity is open. The purpose of this review is to critically examine the current literature evaluating the influence of genetic and environmental factors such as unwanted drug-drug interaction affecting clopidogrel and prasugrel antiplatelet activity.     

Identification of the Significant Involvement and Mechanistic Role of CYP3A4/5 in Clopidogrel Bioactivation

相似文献   

The impact of genetic polymorphisms of P2Y12, CYP3A5 and CYP2C19 on clopidogrel response variability in Iranian patients

Clopidogrel is an inhibitor of platelet ADP P2Y12 receptors and currently used for prevention of stent thrombosis. Despite certain clinical benefit using this drug in patients undergoing percutaneous coronary intervention (PCI), some patients do not attain adequate antiplatelet effects. In this study, we investigated the role of three genetic factors (P2Y12, CYP3A5, CYP2C19), demographic characteristics, and pathologic condition on clopidogrel response variability in Iranian patients after PCI. Patients who were candidate for elective PCI were enrolled in this study. All patients had received aspirin 80-325 mg daily for ≥ 1 week before PCI. Blood samples were taken from patients at baseline, 2 h after taking a 600-mg loading dose of clopidogrel, 24h and 30 days after PCI. Platelet aggregation was measured by turbidimetric aggregation assay with two different concentrations of ADP (5 and 20 μM). CYP2C19*2(rs4244285), CYP2C19*3(rs4986893), CYP3A5 (A6986G), and P2Y12 (T744C) genotypings were performed by PCR-RFLP. One hundred and twelve patients were included in this study. Maximum clopidogrel non-responsiveness (25.90%) occurred at 2 h after taking 600 mg of the loading dose of clopidogrel. Although there were no significant associations between clopidogrel responsiveness and polymorphisms of CYP2C19, CYP3A5, and P2Y12 (P > 0.05), subjects who were CYP3A5 genotype expressor had a greater inhibition of platelet aggregation. No significant associations were observed between environmental factors and clopidogrel responsiveness (P > 0.05). Our results showed that P2Y12, CYP3A5, and CYP2C19 polymorphisms along with non-genetic factors were not responsible for the interindividual variability in response to clopidogrel in Iranian population.     

Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel in vitro

BACKGROUND AND PURPOSE

The conversion of clopidogrel to its active metabolite, R-130964, is a two-step cytochrome P450 (CYP)-dependent process. The current investigations were performed to characterize in vitro the effects of different CYP inhibitors on the biotransformation and on the antiplatelet effect of clopidogrel.

EXPERIMENTAL APPROACH

Clopidogrel biotransformation was studied using human liver microsomes (HLM) or specific CYPs and platelet aggregation using human platelets activated with ADP.

KEY RESULTS

Experiments using HLM or specific CYPs (3A4, 2C19) revealed that at clopidogrel concentrations >10 µM, CYP3A4 was primarily responsible for clopidogrel biotransformation. At a clopidogrel concentration of 40 µM, ketoconazole showed the strongest inhibitory effect on clopidogrel biotransformation and clopidogrel-associated inhibition of platelet aggregation with IC₅₀ values of 0.03 ± 0.07 µM and 0.55 ± 0.06 µM respectively. Clarithromycin, another CYP3A4 inhibitor, impaired clopidogrel biotransformation and antiplatelet activity almost as effectively as ketoconazole. The CYP3A4 substrates atorvastatin and simvastatin both inhibited clopidogrel biotransformation and antiplatelet activity, less potently than ketoconazole. In contrast, pravastatin showed no inhibitory effect. As clopidogrel itself inhibited CYP2C19 at concentrations >10 µM, the CYP2C19 inhibitor lansozprazole affected clopidogrel biotransformation only at clopidogrel concentrations ≤10 µM. The carboxylate metabolite of clopidogrel was not a CYP substrate and did not affect platelet aggregation.

CONCLUSIONS AND IMPLICATIONS

At clopidogrel concentrations >10 µM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations ≤10 µM. CYP2C19 inhibition by clopidogrel at concentrations >10 µM may explain the conflicting results between in vitro and in vivo investigations regarding drug interactions with clopidogrel.     

The effect of St John's Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity

Clopidogrel is metabolically activated by cytochrome P450 (CYP) isoenzymes. We evaluated whether St. John's wort (SJW), a CYP2C19 and CYP3A4 inducer, enhances the pharmacodynamic response of clopidogrel. Volunteers (n = 45) were screened for clopidogrel hyporesponsiveness after a 300-mg load. After a 7-day washout, hyporesponders (n = 10) received 14 days of SJW (300 mg 3 times a day) followed by a second 300-mg clopidogrel. Platelet aggregation was measured at 0, 2, 4, and 6 hours postloading; hepatic CYP3A4 activity was simultaneously determined at 0 and 4 hours by the erythromycin breath test. A prospective, randomized, double-blind pilot study was conducted in postcoronary stent patients (n = 85) on clopidogrel 75 mg/d screened for clopidogrel hyporesponsiveness. Hyporesponders (n = 20) were randomized to SJW (n = 10) or placebo (n = 10); platelet aggregation was measured before and after 14 days of therapy. In volunteers, SJW decreased platelet aggregation (59% ± 14% vs. 40% ± 15% at 2 hours, P = 0.02; 56% ± 10% vs. 44% ± 13% at 4 hours, P < 0.03; and 55% ± 14% vs. 37% ± 14% at 6 hours, P = 0.01) and increased CYP3A4 activity (2.1% ± 0.4% CO2 exhaled per hour before vs. 2.9% ± 0.6% CO2 exhaled per hour after SJW, P = 0.002). In patients, SJW decreased platelet reactivity (226 ± 39 vs. 185 ± 49 P2Y12 reactivity units, P = 0.0002) and increased platelet inhibition (23% ± 11% vs. 41% ± 16%, P = 0.002). SJW may be a future therapeutic option to increase CYP metabolic activity and antiplatelet effect of clopidogrel in hyporesponders.     

冠心病患者中CYP2C19基因多态性与氯吡格雷抵抗及预后相关性研究进展

氯吡格雷是一种临床疗效良好的抗血小板药物,能够显著降低冠心病患者特别是血管支架术后患者的主要不良心血管事件的风险,然而在实际临床应用过程中,部分患者却存在着不同程度的氯吡格雷抵抗现象。氯吡格雷抵抗受多种因素影响,而CYP2C19基因多态性是其最重要的内部因素,合并用药是其主要临床因素之一。该研究对冠心病患者在介入治疗后服用氯吡格雷或合并质子泵抑制剂用药后,发生不良预后是否与CYP2C19基因多态性相关的研究现状进行综述,旨在对氯吡格雷在临床个体化给药方案提供一定的相关参考依据。