支架置入冠状动脉分叉病变后的生物相容性

背景:通过检测CYP2C19基因分型可评估冠状动脉内支架置入患者对氯吡格雷反应性的高低,但目前国内尚缺乏通过检测CYP2C19基因分型指导分叉病变部位支架置入后抗血小板治疗的临床应用。目的:根据CYP2C19基因分型结果,优化冠状动脉分叉病变支架置入后抗血小板治疗方案的效果。方法:纳入136例冠状动脉分叉病变支架置入患者,于支架置入前进行阿司匹林联合氯吡格雷抗血小板治疗,7 d后检测CYP2C19基因分型。若CYP2C19基因分型为*1/*1的作为合格组,支架置入后服用氯吡格雷75 mg/d;若CYP2C19基因分型为*2/*2、*2/*3、*3/*3的作为不合格组,再随机分为2组,一组为常规剂量组,支架置入后即保持氯吡格雷75 mg/d治疗不变,另一组为大剂量组,即增加氯吡格雷剂量为150 mg/d长期服用。随访9个月记录主要心脏不良事件和出血事件发生情况。结果与结论:发生主要心脏不良事件14例中,合格组6例(7.9%)、常规剂量组6例(17.7%)、大剂量组2例(7.7%),合格组发生率明显低于常规剂量组(P<0.05),提示CYP2C19基因分型有较好预测主要心脏不良事件的价值;大剂量组发生率明显小于常规剂量组(P<0.05),说明在CYP2C19基因分型监测下增加抗血小板药物剂量,能明显降低主要心脏不良事件的发生率;大剂量组发生率与合格组比较差异无显著性意义(P>0.05),提示通过检测CYP2C19基因分型,优化氯吡格雷剂量可达到与合格组相同的临床效果。3组出血事件发生率比较差异无显著性意义(P>0.05),提示通过检测CYP2C19基因分型抗血小板治疗不会增加出血风险。     

CYP2C19基因多态性与氯吡格雷抵抗的研究进展

阿司匹林联合氯吡格雷是冠状动脉支架植入术后常规的抗血小板治疗方案。然而,近年来的研究显示接受上述治疗的部分患者血小板的抑制率较低,即氯吡格雷抵抗,与冠脉支架植入术后支架内血栓事件的发生存在因果关系。而导致氯吡格雷抵抗的原因复杂,研究表明CYP2C19基因多态性与其明显相关,对高危人群进行CYP2C19基因多态性检测有利于识别氯吡格雷抵抗,并及时增加氯吡格雷剂量或更换新型血小板P2Y12受体拮抗剂,可降低术后支架内血栓的发生。     

PCI术后6月氯吡格雷反应与CYP2C19基因多态性关系的研究

氯吡格雷在临床中的应用比较广泛,它属于抗血小板药物,通常同阿司匹林联合使用。患者行PCI（经皮冠状动脉介入治疗）术后,通过使用氯吡格雷,有利于控制心血管疾病发生率,防止支架内血栓的形成[1]。就抗血板药物而言,患者的反应存在个体差异,部分患者用药之后,可能未充分抑制血小板,难以取得理想效果[2]。CYP2C19属于红细胞色素P450的主要代谢酶之一,在氯吡格雷氧化代谢作用中,CYP2C19是关键。本文主要分析PCI术后6月氯吡格雷反应与CYP2C19基因多态性关系,现将研究情况报告如下。     

氯吡格雷基因检测在颅内动脉瘤SAC术后的效果观察

目的:探讨药物基因检测指导氯吡格雷用药在支架辅助治疗颅内动脉瘤的应用效果。方法:选取2013年10月~2017年10月我院收治的颅内动脉瘤患者60例,其中43例为住院期间行支架辅助弹簧圈栓塞术(SAC)治疗,并行氯吡格雷药物基因检测,17例行SAC术后回院复查期间实施氯吡格雷药物基因检测,包括CYP2C19*2、CYP2C19*3、CYP2C19*17、AB-CB1-3435C共4个基因位点。分析药物基因检测指导氯吡格雷用药在SAC治疗颅内动脉瘤的应用效果。结果:43例住院患者中20例患者基因型异常,常规剂量氯吡格雷用药未得到理想抗血小板聚集效果,均根据检测结果调整用药方案,基因检测用药指导干预率为46.51%,4例患者出现血栓栓塞并发症表现;17例随访患者中2例出现血栓栓塞并发症表现,均经溶栓治疗后得以缓解。结论 :氯吡格雷药物基因检测对SAC术后的双抗治疗具有指导意义,可为临床用药提供个性化建议,临床应用价值显著。     

PCI术后患者抗血小板药抵抗的临床分析

目的:探讨PCI术后患者双联抗血小板治疗过程中药物抵抗的发现和处理方法。方法:51例PCI术后规律接受双联抗血小板(阿司匹林和氯吡格雷)治疗发生皮肤异常改变者,检测其残余血小板聚集率(RPA),据RPA分为阿司匹林抵抗(AR)组、氯吡格雷抵抗(CR)组、阿司匹林与氯吡格雷抵抗(AR+CR)组,AR组加服阿司匹林50 mg,CR组加服氯吡格雷75 mg,AR+CR组将氯吡格雷换成普拉格雷60 mg负荷量后每日服10 mg。观察一周后RPA变化和皮肤异常改变情况。结果:46例存在抗血小板药抵抗,占90.1%。调整药物后,AR组抵抗无改善,CR、AR+CR组抵抗改善。皮肤异常改变恢复既往状态。结论:PCI术后患者双联抗血小板治疗过程中,可发生抗血小板药抵抗,加大氯吡格雷剂量或换用普拉格雷可改善抵抗。     

MALDI-TOFMS在氯吡格雷基因多态性检测中的应用

目的探讨基因多态性与氯吡格雷个体化用药的相关性及基质辅助激光解析电离飞行时间质谱(MALDI-TOF MS)在氯吡格雷基因多态性检测中的应用价值。方法选取2015-2017年武警重庆总队医院住院的急性冠状动脉综合征(ACS)及拟进行经皮冠状动脉介入术(PCI)的患者160例,在氯吡格雷抗血小板治疗后第5天测定血小板聚集率;同时采用MALDI-TOF MS技术检测CYP2C19*2*、CYP2C19*3、CYP2C19*4、CYP2C19*5、CYP2C19*17和ABCBI、PON1、CES1基因多态性。结果根据血小板最大聚集率(MAR)将研究对象分为氯吡格雷抵抗(CR)组(n=75)和非氯吡格雷抵抗(NCR)组(n=85)。160份样本等位基因检出率为100%,两组均未发现CYP2C19*4、CYP2C19*5、CYP2C19*17突变;携带CYP2C19*2等位基因A及CYP2C19*1/*2、CYP2C19*1/*3、CYP2C19*2/*2、CYP2C19*2/*3代谢型发生氯吡格雷抵抗的风险较高,携带ABCB1等位基因A的GA、AA代谢型发生氯吡格雷抵抗风险较高,携带PON1等位基因T的CT、TT代谢型发生氯吡格雷抵抗的风险较高,携带CES1等位基因T的CT、TT代谢型发生氯吡格雷抵抗的风险较低,差异均有统计学意义(P0.05);携带CYP2C19*3等位基因A发生氯吡格雷抵抗风险较高,CYP2C19*3/*3型发生氯吡格雷的风险较低,差异均无统计学意义(P0.05)。结论 CYP2C19*2、ABCBI、PON1基因突变增加氯吡格雷抵抗的风险,CES1基因突变降低氯吡格雷抵抗风险;MALDI-TOF MS具有准确性高、检测通量大、速度快、成本低等特点,适用于氯吡格雷基因多态性检测,指导临床个体化用药。     

CYP2C19基因多态性在冠心病经皮冠状动脉介入术后一年的随访研究

目的观察替格瑞洛和氯吡格雷的临床疗效,并探讨其与CYP2C19基因多态性的关系。方法入选2016年4月至2017年5月在中国科技大学附属第一医院接受住院治疗并行经皮冠状动脉介入术(PCI)的急性冠脉综合征患者492例,所有患者均接受CYP2C19基因型检测,根据患者口服抗血小板聚集药物分为氯吡格雷组和替格瑞洛组。随访1年,观察两组患者主要心脏不良事件(MACE)和出血并发症的发生率。根据CYP2C19基因检测将两组分别分为三个亚组:快代谢型(CYP2C19*1/*1)、中代谢型(CYP2C19*1/*2、CYP2C19*1/*3)和慢代谢型(CYP2C19*2/2*、CYP2C19*2/3*、CYP2C19*3/3*),分别观察各亚组患者的MACE发生率和治疗期间出血并发症的发生情况。结果替格瑞洛组和氯吡格雷组一年的死亡率、心肌梗死、心绞痛、脑梗死差异均无统计学意义,大中等量出血并无增加,小出血替格瑞洛组较氯吡格雷组有增加趋势,但差异无统计学意义。亚组分析中,替格瑞洛组与氯吡格雷组中的CYP2C19慢、中、快代谢相比,各亚组中一年的死亡率、心肌梗死、心绞痛、脑梗死差异均无统计学意义,大中等量出血并无增加,小出血替格瑞洛组较氯吡格雷组有增加趋势,但差异无统计学意义。结论替格瑞洛和氯吡格雷抗血小板聚集疗效及预后不受CYP2C19基因多态性的影响。     

急性缺血性脑卒中患者CYP2C19基因分型与 临床预后的相关性分析

目的:探讨急性缺血性脑卒中患者CYP2C19基因分型与临床预后的相关性。方法:选取应用氯吡格雷治疗的急性缺血性脑卒中患者156例,进行CYP2C19*2和CYP2C19*3基因型检测,根据检测结果分为野生型组(GG)和突变型组(GA/AA)。对比2组的血小板抑制率、氯吡格雷疗效及临床预后情况。结果:野生型组患者的平均血小板抑制率为(42.42±2.74)%,突变型组为(32.41±2.69)%,突变型组的平均血小板抑制率低于野生型组(P0.05)。突变型组的氯吡格雷抵抗发生率为26.32%,显著高于野生型组的1.25%(P0.05)。突变型组的预后不良发生率高于野生型组,卒中复发率及心脑血管不良事件总发生率也高于野生型组(P0.05)。与野生型组相比,突变型组患者随访期间累积无再发心脑血管不良事件的生存率明显更低(P0.05)。结论:急性缺血性脑卒中患者的CYP2C19基因分型与血小板抑制率、临床预后密切相关,携带CYP2C19突变型基因型的患者,血小板抑制率更低,氯吡格雷敏感性越差,预后不良风险越高。     

血栓弹力图检测氯吡格雷药效与CYP2C19基因型的相关性分析

目的研究临床血栓弹力图检测氯吡格雷药效与CYP2C19基因型的相关性及对PCI术后氯吡格雷治疗的指导意义。方法选择2016年12月至2017年4月于我院心血管内科行PCI治疗的冠心病且术后阿司匹林和氯吡格雷双联抗血小板药物治疗的患者共230例,检测患者血栓弹力图检测结果及CYP2C19的基因型,比较氯吡格雷抵抗组和氯吡格雷敏感组患者的血小板抑制率与CYP2C19基因型的相关性。结果本实验受试者为230人,其中,氯吡格雷抵抗组(94例)和氯吡格雷敏感组(136例); CYP2C19基因型为慢代谢型(107例),非慢代谢型(快代谢型+中间代谢型)共(123例)。利用血栓弹力图测定的ADP抑制率及MA-ADP相关结果,预测CYP2C19基因型的ROC曲线下面积(AUC)分别为:ADP抑制率:0. 663(95%CI:0. 598—0. 723,P0. 001),当ADP抑制率取最佳临界值(31. 26%)时,诊断CYP2C19基因型为慢代谢型的敏感性为80. 49%,特异性为50. 77%; MA-ADP:0. 635(95%CI:0. 570—0. 697,P0. 001),当MA-ADP取最佳临界值(26. 35)时,诊断CYP2C19基因型为慢代谢型的敏感性为56. 10%,特异性为70. 26%。结论血栓弹力图所得ADP抑制率及MA-ADP与CYP2C19慢代谢型有较好的相关性,对指导PCI术后的抗血小板治疗指导意义。     

CYP2C19、PON1基因多态性与氯吡格雷在ACS行PCI术后血小板抑制功能的关联分析

目的探讨CYP2C19、PON1基因多态性与氯吡格雷在急性冠脉综合征(ACS)行经皮冠状动脉介入治疗(PCI)术后血小板抑制功能的相关性。方法回顾性分析2016年6月至2017年5月该院ACS行PCI患者636例,按使用抗血小板药物分为氯吡格雷组(491例)和替格瑞洛组(145例)。采用荧光检测仪检测CYP2C19*2、CYP2C19*3、CYP2C19*17、ABCB1、PON1基因;血栓弹力图仪(TEG)检测服药24h后血小板抑制功能,采用t检验和方差分析比较各组血小板抑制率的差异,逻辑回归分析基因型与抗血小板反应性的关联。结果基因型分析显示CYP2C19功能缺失型等位基因*2、*3至少1个单核苷酸多态性(SNP)位点突变率分别为55.6%和7.2%,功能增强型等位基因*17的突变率为0.6%。ABCB1与PON1基因位点突变率基本相同,分别为60.5%和59.4%。TEG检测二磷酸腺苷(ADP)诱导的血小板抑制率:替格瑞洛组较氯吡格雷组高,差异有统计学意义(t=5.75,P0.05),其中比较两组快代谢型ADP抑制率差异无统计学意义(t=1.92,P0.05),而中间代谢型与慢代谢型差异有统计学意义(t=5.06,P0.05;t=2.03,P0.05)。逻辑回归分析患者基本临床信息与替格瑞洛组基因多态性对药物ADP诱导血小板反应性的影响均无统计学意义(P0.05),而氯吡格雷组携带1个CYP2C19功能缺失型等位基因与ABCB1基因对反应性的影响也均无统计学意义(P0.05),携带两个CYP2C19功能缺失型等位基因或至少携带1个PON1突变基因对预测低反应性风险差异有统计学意义(OR:6.622,95%CI:2.283~19.210,P0.05;OR:2.620,95%CI:1.074~6.393,P=0.034;OR:3.503,95%CI:1.104~11.113,P=0.033)。结论对于ACS行PCI的患者,检测CYP2C19功能缺失型等位基因与PON1基因对预测氯吡格雷抗血小板低反应性风险具有重要意义。     

Differential impacts of CYP2C19 gene polymorphisms on the antiplatelet effects of clopidogrel and ticlopidine

We examined the influence of CYP2C19 polymorphisms on the antiplatelet effects of clopidogrel and ticlopidine. The platelet aggregation induced by 20 μmol/l adenosine diphosphate (ADP) and CYP2C19 single-nucleotide polymorphisms (*2 and *3) was determined in patients with coronary artery disease (CAD) who were taking aspirin alone (n = 21), aspirin plus clopidogrel (n = 97), or aspirin plus ticlopidine (n = 47). The degree of platelet aggregation in the clopidogrel group, although not in the ticlopidine group, depended on the CYP2C19 polymorphism, and the maximal platelet aggregation in poor metabolizers (PMs) taking clopidogrel was equivalent to that in the group taking aspirin alone. After being switched from clopidogrel to ticlopidine, all seven of the PMs showed markedly lower platelet aggregation. These results suggest that CYP2C19 polymorphisms have a profound impact on the antiplatelet effect of clopidogrel but not on that of ticlopidine. Ticlopidine may be an effective therapeutic option for CYP2C19 PMs.     

The future of platelet function testing to guide therapy in clopidogrel low and enhanced responders

Dual oral antiplatelet therapy with aspirin and clopidogrel is the therapy of choice in patients with acute coronary syndromes and in patients undergoing coronary stent placement to lower the risk of thrombotic events. Responsiveness to aspirin and especially to clopidogrel is not uniform and is subject to considerable interindividual variability. Furthermore, there is a broad consensus that clopidogrel low response or so-called high on-treatment platelet reactivity is linked to the occurrence of ischemic events. On the other hand, evidence is accumulating that enhanced clopidogrel responders are at increased risk of bleeding. Newer antiplatelet drugs, such as prasugrel and ticagrelor, are more potent and produce more consistent inhibition of platelet aggregation via the P2Y(12) ADP platelet receptor. A variety of methods of platelet function testing are available for evaluating platelet inhibition in percutaneous coronary intervention-treated patients in order to help determine the individual risk for ischemic and bleeding complications. Although not yet routinely undertaken, platelet function testing offers the potential to tailor antiplatelet therapy for individual patients. Whether alteration of therapy based on platelet function testing improves patients' outcomes remains unclear and is currently under investigation. This article reviews the impact of antiplatelet drug responsiveness on clinical outcomes with a focus on P2Y(12) receptor inhibition as well as on current and future concepts for personalized antiplatelet strategies.     

Personalizing antiplatelet prescribing using genetics for patients undergoing percutaneous coronary intervention

Introduction. Clopidogrel is commonly prescribed with aspirin to reduce the risk for adverse cardiovascular events after percutaneous coronary intervention (PCI). However, there is significant inter-patient variability in clopidogrel response. The CYP2C19 enzyme is involved in the biotransformation of clopidogrel to its pharmacologically active form, and variation in the CYP2C19 gene contributes to clopidogrel response variability.

Areas covered. This article describes the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics, and effectiveness. Examples of clinical implementation of CYP2C19 genotype-guided antiplatelet therapy for patients undergoing PCI are also described as are emerging outcomes data with this treatment approach.

Expert commentary. A large clinical trial evaluating outcomes with CYP2C19 genotype-guided antiplatelet therapy after PCI is on-going. In the meantime, data from pragmatic and observational studies and smaller trials support improved outcomes with genotyping after PCI and use of alternative antiplatelet therapy in patients with a CYP2C19 genotype associated with reduced clopidogrel effectiveness.     

基于武汉地区PCI术后患者CYP2C19基因多态性指导氯吡格雷个体化用药的研究

目的研究CYP2C19基因多态性,分析经皮冠状动脉介入治疗(PCI)术后氯吡格雷中、慢代谢患者个体化用药的疗效差异,为PCI术后患者个体化用药提供参考依据。方法使用荧光定量PCR法测定该院328例PCI术后患者CYP2C19基因型,分析年龄、性别与CYP2C19基因多态性的关系及不同地区汉族冠心病患者代谢表型差异,比较中、慢代谢型患者维持原方案(服用氯吡格雷)和更换抗血小板药物治疗之间的疗效差异。结果本研究共检测出7种基因型,分别为CYP2C19*1*17、*1*1、*1*2、*1*3、*2*17、*2*2、*2*3;4种代谢表型,分别为超快代谢型(1.22%)、快代谢型(42.38%)、中代谢型(40.85%)、慢代谢型(15.55%);代谢表型与太原、连云港地区汉族冠心病患者比较差异有统计学意义(P<0.05),与其他地区汉族冠心病患者比较差异无统计学意义(P>0.05);不同性别患者CYP2C19基因分型、代谢表型差异无统计学意义(P=0.646、0.246);不同年龄段患者CYP2C19基因分型、代谢表型差异无统计学意义(P=0.823、0.574);中、慢代谢型患者维持原方案与更换抗血小板药物治疗比较,疗效差异无统计学意义(P=0.538)。结论本研究中的武汉地区汉族PCI术后患者以中、快代谢型为主,等位基因频率符合亚洲人群分布,对于中、慢代谢型患者,更换抗血小板药物未降低心血管不良事件发生率。     

Prasugrel vs. clopidogrel for cytochrome P450 2C19‐genotyped subgroups: integration of the TRITON‐TIMI 38 trial data

Summary. Background: Prasugrel is a newly marketed antiplatelet drug with improved cardiac outcomes as compared with clopidogrel for acute coronary syndromes involving percutaneous coronary intervention (PCI). Analysis of a subset of the TRITON‐TIMI 38 trial demonstrated that cytochrome P450 2C19 (CYP2C19) reduced‐function genotypes are associated with differential clinical responses to clopidogrel, but not prasugrel. Whether the CYP2C19 genotype has the potential to influence clinical choice of these drugs prior to PCI for individuals with unstable angina or non‐ST segment elevation myocardial infarction is currently uncertain. Methods and Results: An exploratory, secondary analysis was undertaken to estimate the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype, by integrating the published results of the genetic substudy and the overall TRITON‐TIMI 38 trial. Individuals with a CYP2C19 reduced‐metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction, or stroke) with prasugrel as compared with clopidogrel [relative risk (RR) 0.57; 95% confidence interval (CI) 0.39–0.83]. For CYP2C19 extensive metabolizers (～ 70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (RR 0.98; 95% CI 0.80–1.20). Conclusions: Integration of the TRITON‐TIMI 38 data suggests that the CYP2C19 genotype can discriminate between individuals who receive extensive benefit from using prasugrel instead of clopidogrel, and individuals with comparable clinical outcomes with prasugrel and clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet therapy, and further research is warranted to validate this estimate.     

Individual variability in the disposition of and response to clopidogrel: pharmacogenomics and beyond

The widespread use of clopidogrel alone or in combination with aspirin has significantly benefited patients with acute coronary syndrome who are managed medically or by percutaneous coronary intervention and stent implantation, greatly improving their survival. Emerging data have documented that the clopidogrel response may vary from person to person and even from disease to disease, and that genetic and nongenetic factors contribute to that variability. Genetic polymorphisms affecting clopidogrel metabolic bioactivation and platelet function may be responsible, each exerting a small effect. CYP2C19 *2, *3 and *17, CYP2C9 *2 and *3, MDR1*2, and functional variants in the genes encoding platelet membrane receptors and intracellular signaling proteins are involved, and other genetic factors remain to be identified. In addition, nongenetic factors may be influential covariates, such as ethnicity, gender, age, body weight, co-existing diseases, drug-drug interactions, and other factors to be determined. Each piece of the puzzle would be useful to bridge and delineate identified knowledge gaps and to determine future research needs for the risk prediction of fatal complications associated with inadequate clopidogrel therapy in patient care.     

慢性肾脏病合并糖尿病的治疗

慢性肾脏病(CKD)合并糖尿病的治疗措施包括生活方式干预、降糖、降压、降脂、抗血小板及肾脏替代治 疗。所有治疗遵循安全、有效、个体化原则。生活方式干预强调低盐低蛋白饮食。治疗药物的选择及剂量的调整应基 于药物的药代动力学特征及肾功能水平。降糖药利格列汀、格列吡嗪、吡格列酮可全程应用于CKD无需调整剂量。 降压治疗首选肾素血管紧张素醛固酮系统阻滞剂。对于CKDG1~4期患者,推荐启用他汀类药物。抗血小板治 疗首选阿司匹林,不能耐受或有禁忌证者以氯吡格雷替代。透析启动时机与非糖尿病CKD患者相同。     

Genetic testing in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a cost‐effectiveness analysis

Summary. Background: The CYP2C19 genotype is a predictor of adverse cardiovascular events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) treated with clopidogrel. Objectives: We aimed to evaluate the cost‐effectiveness of a CYP2C19*2 genotype‐guided strategy of antiplatelet therapy in ACS patients undergoing PCI, compared with two ‘no testing’ strategies (empiric clopidogrel or prasugrel). Methods: We developed a Markov model to compare three strategies. The model captured adverse cardiovascular events and antiplatelet‐related complications. Costs were expressed in 2010 US dollars and estimated using diagnosis‐related group codes and Medicare reimbursement rates. The net wholesale price for prasugrel was estimated as $5.45 per day. A generic estimate for clopidogrel of $1.00 per day was used and genetic testing was assumed to cost $500. Results: Base case analyses demonstrated little difference between treatment strategies. The genetic testing‐guided strategy yielded the most QALYs and was the least costly. Over 15 months, total costs were $18 lower with a gain of 0.004 QALY in the genotype‐guided strategy compared with empiric clopidogrel, and $899 lower with a gain of 0.0005 QALY compared with empiric prasugrel. The strongest predictor of the preferred strategy was the relative risk of thrombotic events in carriers compared with wild‐type individuals treated with clopidogrel. Above a 47% increased risk, a genotype‐guided strategy was the dominant strategy. Above a clopidogrel cost of $3.96 per day, genetic testing was no longer dominant but remained cost‐effective. Conclusions: Among ACS patients undergoing PCI, a genotype‐guided strategy yields similar outcomes to empiric approaches to treatment, but is marginally less costly and more effective.     

The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance

We evaluated the effect of the CYP2C19 genotype on the pharmacokinetics and pharmacodynamcis of clopidogrel. Twenty-four subjects were divided into three groups on the basis of their CYP2C19 genotype: homozygous extensive metabolizers (homoEMs, n = 8), heterozygous EMs (heteroEMs, n = 8), and poor metabolizers (PMs, n = 8). After a single 300-mg loading dose of clopidogrel on day 1, followed by a 75-mg daily maintenance dose from days 2 to 7, we measured the plasma levels of clopidogrel and assessed the antiplatelet effect as pharmacodynamics. The mean clopidogrel area under the curve (AUC) for PMs was 1.8- and 2.9-fold higher than that for heteroEMs and homoEMs, respectively (P = 0.013). The mean peak plasma concentration in PMs was 1.8- and 4.7-fold higher than that of heteroEMs and homoEMs, respectively (P = 0.008). PMs exhibited a significantly lower antiplatelet effect than heteroEMs or homoEMs (P < 0.001). From these findings it is clear that the CYP2C19 genotype affects the plasma levels of clopidogrel and modulates the antiplatelet effect of clopidogrel.