氯吡格雷与质子泵抑制剂相互作用研究
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摘要
目的观察氯吡格雷（clopidogrel，CLP）及其羧酸代谢物（SR26334）、奥美拉唑（omeprazole，OMZ）对人脐静脉内皮细胞（human umbilical vein endothelial cell，HUVEC）全基因表达谱的影响；评价20mg奥美拉唑和10mg雷贝拉唑（rabeprazole，RPZ）对健康志愿者75mg氯吡格雷稳态血药浓度及药效学的影响；回顾性分析质子泵抑制剂（proton pump inhibitor，PPI）对老年冠心病（coronaryartery disease，CAD）患者氯吡格雷治疗预后的影响。
方法第一部分10-5mol/L氯吡格雷及其羧酸代谢物、奥美拉唑分别与人脐静脉内皮细胞株共培养48h，运用Affymetrix HU133Aplus2.0全基因组表达芯片，检测三种药物成分对人脐静脉内皮细胞基因表达谱的影响，分子注释系统MAS3.0软件对差异表达基因进行聚类分析。实时定量多聚酶链反应(real timepolymerase chain reaction，RT-PCR)验证基因表达谱结果，Western blotting验证相关蛋白水平的变化。第二部分18名中国健康成年志愿者入选三阶段交叉研究，随机给予氯吡格雷75mg、氯吡格雷75mg+奥美拉唑20mg或氯吡格雷75mg+雷贝拉唑10mg，每日1次，连续服药1周，洗脱期2周。每阶段第7天服药后4小时采取血样进行氯吡格雷羧酸及活性代谢物浓度检测。光比浊血小板聚集实验（light transmittance aggregometry，LTA）和血管舒张因子激活的磷酸蛋白磷酸化法（vasodilator-stimulated phosphoprotein，VASP）分别检测最大血小板聚集率（maximal platelet aggregation，MPA)和血小板反应指数（platelet reactivity index，PRI）。第三部分回顾2001年1月1日～2011年2月28日解放军总医院老年病房服用氯吡格雷冠心病患者合并使用质子泵抑制剂情况及相关临床特征，一级终点为全因死亡，次级终点为心绞痛发作、再发心肌梗死（myocardial infarction，MI）、接受再血管化治疗、脑卒中、短暂性脑缺血发作（transient ischemic attack，TIA）等心血管事件及出血并发症。
结果第一部分氯吡格雷作用内皮细胞48h后，基因芯片分析筛选出差异表达大于1.5倍的基因508个，其中上调基因139个，下调基因369个，基因功能涉及蛋白结合、转录因子活性、锌离子结合、DNA依赖的转录的调节、转录、RNA剪接等生物过程；通过氯吡格雷羧酸作用，脐静脉内皮细胞差异表达大于1.5倍的基因235个，其中上调基因176个，下调基因59个，包括DNA依赖的转录调节、转录、从RNA聚合酶II启动子开始转录的正调节、细胞周期、细胞分割、蛋白氨基酸去磷酸化等相关基因；奥美拉唑作用下，差异表达大于1.5倍的基因282个，其中上调基因236个，下调基因46个，基因功能聚类涉及转录调节、炎症反应、免疫反应、细胞粘附、抗凋亡、信号转导等生物过程。RT-PCR和Western blotting结果与基因芯片结果一致。第二部分与基线水平相比，75mg氯吡格雷使志愿者血小板聚集率显著降低，20mg奥美拉唑和10mg雷贝拉唑的使用减弱了氯吡格雷的抗血小板作用。氯吡格雷抗血小板活性与其血浆活性代谢物浓度明显相关，与羧酸代谢物浓度无线性相关关系。第三部分共入组分析服用氯吡格雷的老年冠心病患者1033名，单用氯吡格雷739例，氯吡格雷联用PPI294例(奥美拉唑170例，雷贝拉唑112例，埃索美拉唑12例)。单用氯吡格雷与合用PPI两组患者全因死亡的发病密度分别为3.54/1000人月和4.23/1000人月，OR1.196(95%CI:0.777-1.842，P＞0.05)，终点事件发病密度比较无显著差异（P>0.05）；对所有混杂因素进行倾向评分，采用加权分析的方法再次比较，氯吡格雷联用PPI较单用氯吡格雷全因死亡率及终点事件发生率无显著差异（P>0.05）。Kaplan-Meier分析显示不同PPI对服用氯吡格雷患者生存和终点事件影响无明显差异（P>0.05）。
结论氯吡格雷及其羧酸代谢物、奥美拉唑对体外培养的脐静脉内皮细胞基因表达产生一定的影响，提示奥美拉唑和氯吡格雷除抗血小板方面的相互作用外，还通过多条通路影响内皮细胞的功能；奥美拉唑和雷贝拉唑通过减少氯吡格雷活性代谢产物的形成，减弱氯吡格雷的抗血小板作用；服用氯吡格雷的老年冠心病患者，合用PPI(主要是奥美拉唑和雷贝拉唑)对患者生存和心血管事件的发生没有明显影响，这一结果在对混杂因素进行倾向评分加权分析后没有改变。
Objective: To characterize the effect of clopidogrel and its carboxylic acid metabolite, omeprazoleon the spectrum of gene expression in the cultrured human umbilical vein endothelial cell(HUVEC) line (EA.hy926), and preliminarily explore the potential molecular mechanism of thecompounds on HUVEC; To evaluate impact of20mg omeprazole and10mg rabeprazole onplasma concentration and pharmacodynamics of75mg clopidogrel in Chinese healthy volunteers;To investigate outcomes of clopidogrel therapy combined with proton pump inhibitor（PPI）inelderly patients with coronary artery disease(CAD).
Methods: Part Ⅰ Affymetrix HU133A plus2.0oligonucleotide microarray was used to detectthe alteration in the gene expression profiles induced48h by1×10-5mol/L clopidogrel and itscarboxylic acid metabolite, meprazole in HUVEC. Clustering analysis of differentially expressedgenes was performed with MAS (Molecule Annotation System) version3.0. Real-time PCR wasemployed to verify the results of selected differentially expressed genes, and Western blotting wasperformed to test the expression levels of the related proteins. Part Ⅱ Eighteen Chinese healthyvolunteers were enrolled in the three-period crossover study, following below drug regimen: oralclopidogrel75mg alone; clopidogrel75mg combined with omeprazole20mg; or clopidogrel75mgplus rabeprazole10mg once a day for1week, the washout period is2weeks. Blood samples weretaken4hrs after dose every7thday of the treatment, Plasma concentration of active metabolite andcarboxylic acid metabolite of clopidogrel was test, Maximal platelet aggregation (MPA) andplatelet reactivity index (PRI) was assessed using light transmittance aggregometry (LTA) andvasodilator-stimulated phosphoprotein (VASP) respectively. Part Ⅲ We conducted aretrospective cohort study of hospitalized coronary artery disease (CAD) patients aged60years orolder who commenced clopidogrel between January.1,2001, and February.28,2011, toevaluate adverse clinical outcomes possibly related to using clopidogrel plus a PPI compared withclopidogrel alone. The primary endpoint was all cause death, the secondary endpoint were nonfatal myocardial infarction (MI), and hospitalization for unstable angina, stroke, transientischemic attack(TIA), repeat revascularization (Percutaneous coronary intervention, PCI orcoronary artery bypass graft, CABG), or bleeding complications.
Results: PartⅠ Total508including139up-regulated and369down-regulated genes wereobtained with fold change more than1.5after clopidogrel (10-5M) acted on HUVEC for48hours.Affected genes involved in protein binding, transcription factor activity, zinc ion binding,regulation of transcription, transcription, RNA splicing in HUVEC; After SR26334(10-5M)treated,235including176up-regulated and59down-regulated genes were obtained with foldchange more than1.5SR26334affected the expression levels of genes involving in regulation oftranscription, transcription, positive regulation of transcription from RNA polymerase II promoter,cell cycle, cell division, protein amino acid dephosphorylation; After omeprazole (10-5M) treated,total282including236up-regulated and46down-regulated genes were obtained with fold changemore than1.5fold. Affected genes involved in bioprocess of regulation of transcription,inflammatory response, immune response, cell adherence, anti-apoptosis, signal transduction inHUVEC. RT-PCR and Western blotting verified the results of selected gene expression. Part ⅡCLopidogrel75mg inhibited platelet aggregation of the volunteers significantly compared withtheir baseline level. Omeprazole20mg and rabeprazole10mg weakened antiplatelet effect ofclopidogrel. There was a significant linear correlation between antiplatelet effect and activemetabolite plasma concentration of clopidogel, but no such linear correlation between antiplateleteffect and level of its carboxylic acid metabolite. PartⅢ1033old CAD patients undercontinuous clopidogrel therapy were enrolled,739were prescribed clopidogrel solely and249were administrated clopidogrel combined with PPI(omeprazole170, rabeprazole112andesomeprazole12). The incidence density of all cause death of clopidogrel group and clopidogrelplus PPI group was3.54/1000person-months和4.23/1000person-month respectively, OR1.196(95%CI:0.777-1.842, P=0.415); The incidence density of composite thromboembolic eventswasn’t statistical significance (P=0.492). After propensity scored all listed confounders and weightthe incidence data with the score, further analysis still did not show any difference in mortalityand end point events between the two group（sP>0.05）. Kaplan-Meier survival analysis showed nodifference of mortality and end point events among the three different PPI（P>0.05）.
Conclusion: Clopidogrel and its carboxylic acid metabolite, omeprazole influence gene expression of cultured HUVEC, which include that clopidogrel and omeprazole both affect thefunction of endothelial cell through different pathway apart from their interaction on the aspect ofantiplatelet; Omeprazole and rabeprazole weaken antiplatelet effect of clopidogrel by decreaseformation of its active metabolite; Clopidogrel with omeprazole, rabeprazole, or esomeprazoledoes not increase all cause mortality and incidence of cardiovascular events in elderly CADpatients compared with those under clopidogrel therapy without any PPI, The results persists afterweighted data with confounders propensity score.
方法第一部分10-5mol/L氯吡格雷及其羧酸代谢物、奥美拉唑分别与人脐静脉内皮细胞株共培养48h，运用Affymetrix HU133Aplus2.0全基因组表达芯片，检测三种药物成分对人脐静脉内皮细胞基因表达谱的影响，分子注释系统MAS3.0软件对差异表达基因进行聚类分析。实时定量多聚酶链反应(real timepolymerase chain reaction，RT-PCR)验证基因表达谱结果，Western blotting验证相关蛋白水平的变化。第二部分18名中国健康成年志愿者入选三阶段交叉研究，随机给予氯吡格雷75mg、氯吡格雷75mg+奥美拉唑20mg或氯吡格雷75mg+雷贝拉唑10mg，每日1次，连续服药1周，洗脱期2周。每阶段第7天服药后4小时采取血样进行氯吡格雷羧酸及活性代谢物浓度检测。光比浊血小板聚集实验（light transmittance aggregometry，LTA）和血管舒张因子激活的磷酸蛋白磷酸化法（vasodilator-stimulated phosphoprotein，VASP）分别检测最大血小板聚集率（maximal platelet aggregation，MPA)和血小板反应指数（platelet reactivity index，PRI）。第三部分回顾2001年1月1日～2011年2月28日解放军总医院老年病房服用氯吡格雷冠心病患者合并使用质子泵抑制剂情况及相关临床特征，一级终点为全因死亡，次级终点为心绞痛发作、再发心肌梗死（myocardial infarction，MI）、接受再血管化治疗、脑卒中、短暂性脑缺血发作（transient ischemic attack，TIA）等心血管事件及出血并发症。
结果第一部分氯吡格雷作用内皮细胞48h后，基因芯片分析筛选出差异表达大于1.5倍的基因508个，其中上调基因139个，下调基因369个，基因功能涉及蛋白结合、转录因子活性、锌离子结合、DNA依赖的转录的调节、转录、RNA剪接等生物过程；通过氯吡格雷羧酸作用，脐静脉内皮细胞差异表达大于1.5倍的基因235个，其中上调基因176个，下调基因59个，包括DNA依赖的转录调节、转录、从RNA聚合酶II启动子开始转录的正调节、细胞周期、细胞分割、蛋白氨基酸去磷酸化等相关基因；奥美拉唑作用下，差异表达大于1.5倍的基因282个，其中上调基因236个，下调基因46个，基因功能聚类涉及转录调节、炎症反应、免疫反应、细胞粘附、抗凋亡、信号转导等生物过程。RT-PCR和Western blotting结果与基因芯片结果一致。第二部分与基线水平相比，75mg氯吡格雷使志愿者血小板聚集率显著降低，20mg奥美拉唑和10mg雷贝拉唑的使用减弱了氯吡格雷的抗血小板作用。氯吡格雷抗血小板活性与其血浆活性代谢物浓度明显相关，与羧酸代谢物浓度无线性相关关系。第三部分共入组分析服用氯吡格雷的老年冠心病患者1033名，单用氯吡格雷739例，氯吡格雷联用PPI294例(奥美拉唑170例，雷贝拉唑112例，埃索美拉唑12例)。单用氯吡格雷与合用PPI两组患者全因死亡的发病密度分别为3.54/1000人月和4.23/1000人月，OR1.196(95%CI:0.777-1.842，P＞0.05)，终点事件发病密度比较无显著差异（P>0.05）；对所有混杂因素进行倾向评分，采用加权分析的方法再次比较，氯吡格雷联用PPI较单用氯吡格雷全因死亡率及终点事件发生率无显著差异（P>0.05）。Kaplan-Meier分析显示不同PPI对服用氯吡格雷患者生存和终点事件影响无明显差异（P>0.05）。
结论氯吡格雷及其羧酸代谢物、奥美拉唑对体外培养的脐静脉内皮细胞基因表达产生一定的影响，提示奥美拉唑和氯吡格雷除抗血小板方面的相互作用外，还通过多条通路影响内皮细胞的功能；奥美拉唑和雷贝拉唑通过减少氯吡格雷活性代谢产物的形成，减弱氯吡格雷的抗血小板作用；服用氯吡格雷的老年冠心病患者，合用PPI(主要是奥美拉唑和雷贝拉唑)对患者生存和心血管事件的发生没有明显影响，这一结果在对混杂因素进行倾向评分加权分析后没有改变。
Objective: To characterize the effect of clopidogrel and its carboxylic acid metabolite, omeprazoleon the spectrum of gene expression in the cultrured human umbilical vein endothelial cell(HUVEC) line (EA.hy926), and preliminarily explore the potential molecular mechanism of thecompounds on HUVEC; To evaluate impact of20mg omeprazole and10mg rabeprazole onplasma concentration and pharmacodynamics of75mg clopidogrel in Chinese healthy volunteers;To investigate outcomes of clopidogrel therapy combined with proton pump inhibitor（PPI）inelderly patients with coronary artery disease(CAD).
Methods: Part Ⅰ Affymetrix HU133A plus2.0oligonucleotide microarray was used to detectthe alteration in the gene expression profiles induced48h by1×10-5mol/L clopidogrel and itscarboxylic acid metabolite, meprazole in HUVEC. Clustering analysis of differentially expressedgenes was performed with MAS (Molecule Annotation System) version3.0. Real-time PCR wasemployed to verify the results of selected differentially expressed genes, and Western blotting wasperformed to test the expression levels of the related proteins. Part Ⅱ Eighteen Chinese healthyvolunteers were enrolled in the three-period crossover study, following below drug regimen: oralclopidogrel75mg alone; clopidogrel75mg combined with omeprazole20mg; or clopidogrel75mgplus rabeprazole10mg once a day for1week, the washout period is2weeks. Blood samples weretaken4hrs after dose every7thday of the treatment, Plasma concentration of active metabolite andcarboxylic acid metabolite of clopidogrel was test, Maximal platelet aggregation (MPA) andplatelet reactivity index (PRI) was assessed using light transmittance aggregometry (LTA) andvasodilator-stimulated phosphoprotein (VASP) respectively. Part Ⅲ We conducted aretrospective cohort study of hospitalized coronary artery disease (CAD) patients aged60years orolder who commenced clopidogrel between January.1,2001, and February.28,2011, toevaluate adverse clinical outcomes possibly related to using clopidogrel plus a PPI compared withclopidogrel alone. The primary endpoint was all cause death, the secondary endpoint were nonfatal myocardial infarction (MI), and hospitalization for unstable angina, stroke, transientischemic attack(TIA), repeat revascularization (Percutaneous coronary intervention, PCI orcoronary artery bypass graft, CABG), or bleeding complications.
Results: PartⅠ Total508including139up-regulated and369down-regulated genes wereobtained with fold change more than1.5after clopidogrel (10-5M) acted on HUVEC for48hours.Affected genes involved in protein binding, transcription factor activity, zinc ion binding,regulation of transcription, transcription, RNA splicing in HUVEC; After SR26334(10-5M)treated,235including176up-regulated and59down-regulated genes were obtained with foldchange more than1.5SR26334affected the expression levels of genes involving in regulation oftranscription, transcription, positive regulation of transcription from RNA polymerase II promoter,cell cycle, cell division, protein amino acid dephosphorylation; After omeprazole (10-5M) treated,total282including236up-regulated and46down-regulated genes were obtained with fold changemore than1.5fold. Affected genes involved in bioprocess of regulation of transcription,inflammatory response, immune response, cell adherence, anti-apoptosis, signal transduction inHUVEC. RT-PCR and Western blotting verified the results of selected gene expression. Part ⅡCLopidogrel75mg inhibited platelet aggregation of the volunteers significantly compared withtheir baseline level. Omeprazole20mg and rabeprazole10mg weakened antiplatelet effect ofclopidogrel. There was a significant linear correlation between antiplatelet effect and activemetabolite plasma concentration of clopidogel, but no such linear correlation between antiplateleteffect and level of its carboxylic acid metabolite. PartⅢ1033old CAD patients undercontinuous clopidogrel therapy were enrolled,739were prescribed clopidogrel solely and249were administrated clopidogrel combined with PPI(omeprazole170, rabeprazole112andesomeprazole12). The incidence density of all cause death of clopidogrel group and clopidogrelplus PPI group was3.54/1000person-months和4.23/1000person-month respectively, OR1.196(95%CI:0.777-1.842, P=0.415); The incidence density of composite thromboembolic eventswasn’t statistical significance (P=0.492). After propensity scored all listed confounders and weightthe incidence data with the score, further analysis still did not show any difference in mortalityand end point events between the two group（sP>0.05）. Kaplan-Meier survival analysis showed nodifference of mortality and end point events among the three different PPI（P>0.05）.
Conclusion: Clopidogrel and its carboxylic acid metabolite, omeprazole influence gene expression of cultured HUVEC, which include that clopidogrel and omeprazole both affect thefunction of endothelial cell through different pathway apart from their interaction on the aspect ofantiplatelet; Omeprazole and rabeprazole weaken antiplatelet effect of clopidogrel by decreaseformation of its active metabolite; Clopidogrel with omeprazole, rabeprazole, or esomeprazoledoes not increase all cause mortality and incidence of cardiovascular events in elderly CADpatients compared with those under clopidogrel therapy without any PPI, The results persists afterweighted data with confounders propensity score.
引文
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