新药替卡格雷与普拉格雷及其克服氯吡格雷抵抗的研究进展New drugs ticagrelor and prasugrel and the study progress on the aspect of their anti-clopidogrel resistance acitivity
白汉生,朱晓洁,张予阳
BAI Han-sheng,ZHU Xiao-jie,ZHANG Yu-yang(School of Life Science and Biopharmaceutics
摘要(Abstract):
目的对新型抗血小板凝集药普拉格雷和替卡格雷及它们与原有抗血小板聚集药氯吡格雷的异同及克服氯吡格雷抵抗作用进行综述。方法参阅最新国内外公开发表的相关文献,阐述新药普拉格雷和替卡格雷的研发思路及作用特点,比较它们与原有抗血小板聚集药氯吡格雷的异同,论述其克服氯吡格雷抵抗的作用机制所在。结果相对于氯吡格雷,新型抗血小板聚集药普拉格雷和替卡格雷更加强力有效,并可明显降低甚至避免氯吡格雷抵抗事件的发生。结论国际知名制药公司对普拉格雷和替卡格雷的研发理念可带给我们新启示,这些新型抗血小板聚集药为临床医师提供了新的用药选择。
Objective To introduce the development of prasugrel and ticagrelor which were new antiplatelet drugs,as well as the difference between them and the primary anti-platelet drug clopidogrel and demonstrate that clopidogrel resistance can be overcome by the two drugs.Methods The review was completed based on the latest published literatures.Some research developing ideas and the action characters of prasugrel and ticagrelor were presented.Moreover,pharmacological effects and pharmacokinetic properties of the new drugs and clopidogrel were compared,and the mechanism of the drugs overcoming clopidogrel resistance was also discussed in this review.Results The two new drugs had a stronger potency comparing with clopidogrel and could significantly reduce the occurrence of clopidogrel resistance.Conclusions The developing ideas of prasugrel and ticagrelor can provide us with new enlightenments.In addition,these new anti-platelet drugs can also offer new choices for clinician.
关键词(KeyWords):
普拉格雷;替卡格雷;氯吡格雷抵抗;基因多态性
prasugrel;ticagrelor;clopidogrel resistance;gene polymorphisms
基金项目(Foundation):
作者(Author):
白汉生,朱晓洁,张予阳
BAI Han-sheng,ZHU Xiao-jie,ZHANG Yu-yang(School of Life Science and Biopharmaceutics
DOI: 10.14066/j.cnki.cn21-1349/r.2012.07.008
参考文献(References):
- [1]BRANDT J T,CLOSE S L,ITURRIA S J,et al.Com-mon polymorphisms of CYP2C19and CYP2C9affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel[J].J Thromb Haemost,2007,5(12):2429-2436.
- [2]KAZUI M,NISHIYA Y,ISHIZUKA T,et al.Identi fica-tion of the human cytochrome P450enzymes invo lved in the two oxidative steps in the bioa ctivation of clopi-dogrel to its pharmacologically active metabolite[J].Drug Metab Dispos,2010,38(1):92-99.
- [3]BRANDT J T,PAYNE C D,WIVIOTT S D,et al.A comparison of prasugrel and clopidogrel loading doses on platelet function:magnitude of platelet inhibition is related to active metabolite formation[J].Am Heart J,2007,153(1):66.e9-16.
- [4]WIVIOTT S D,BRAUNWALD E,MCCABE C H,et al.Prasugrel versus clopidogrel in patients with acutecoro-narysyndromes[J].N Engl J Med,2007,357(20):2001-2015.
- [5]KASSIMIS G,DAVLOUROS P,XANTHOPOULOU I,et al.CYP2C19*2and other genetic variants affecting platelet response to clopidogrel in patients undergoing percutaneous coronary intervention[J].Thromb Res,2012,129(4):441-446.
- [6]INGELMAN-SUNDBERG M,SIM S C,GOMEZ A,et al.Influence of cytochrome P450polymorphisms on drug therapies:pharmacogenetic,pharmacoepigenetic and clinical aspects.[J]Pharmacol Ther,2007,116(3):496-526.
- [7]IWASAKI M,SAWADA T,SHINKE T,et al.Repeated intra-stent thrombus formation in a patient with acute coronary syndrome due to poor responsiveness to clopi-dogrel may be associated with cytochrome P-4502C19*2polymorphism[J].J C Cases,2011,3(3):e123-e128.
- [8]HULOT J S,BURA A,VILLARD E,et al.Cytochrome P4502C19loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthysubjects[J].Blood,2006,108(7):2244-2247.
- [9]FARID N A,PAYNE C D,SMALL D S,et al.Cyto-chrome P4503A inhibition by ketoconazole affects pra-sugrel and clopidogrel pharmacokinetics and pharmaco-dynamics differently[J].Clin Pharmacol Ther,2007,81(5):735-741.
- [10]SMALL D S,FARID N A,PAYNE C D,et al.Effects of the proton pump inhibitor lansoprazole on the pharma-cokinetics and pharmacodynamics of prasugrel and clo-pidogrel[J].J Clin Pharmacol,2008,48(4):475-484.
- [11]CRESPIN D J,FEDERSPIEL J J,BIDDLE A K,et al.Ticagrelor versus genotype-driven antiplatelet therapy for secondary prevention after acute coronary syn-drome:a cost-effectiveness analysis[J].Value Health,2011,14(4):483-491.
- [12]HUSTED S,GIEZEN J V.Ticagrelor:The First Revers-ibly Binding Oral P2Y12Receptor Antagonist[J].Car-diovasc Ther,2009,27(4):259-274.
- [13]HUMPHRIES R G.Pharmacology of AR-C69931MX and related compounds:from pharmacological tools to clinical trials[J].Haematologica,2000,85,66-72.
- [14]SPRINGTHORPE B,BAILEY A,BARTON P,et al.From ATP to AZD6140:the discovery of an orally ac-tive reversible P2Y12receptor antagonist for the pre-vention of thrombosis[J].Bioorg Med Chem Lett,2007,17(21):6013-6018.
- [15]WALLENTIN L,BECKER R C,BUDAJ A,et al.Ti-cagrelor versus Clopidogrel in Patients with Acute Cor-onary Syndromes[J].N Engl J Med,2009,361(11):1045-1057.
- [16]BLIDEN K P,TANTRY U S,STOREY R F,et al.The effect of ticagrelor versus clopidogrel on high on-treat-ment platelet reactivity:combined analysis of the ON-SET/OFFSET and RESPOND studies[J].Am Heart J,2011,162(1):160-165.
- [17]GURBEL P A,BLIDEN K P,BUTLER K,et al.Ran-domized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery dis-ease:the ONSET/OFFSET study[J].Circulation,2009,120(25):2577-2585.
- [18]SILLéN H,COOK M,DAVIS P.Determination of un-bound ticagrelor and its active metabolite(AR-C124910XX)in human plasma by equilibrium dialysis and LC-MS/MS[J].J Chromatogr B Analyt Technol Biomed Life Sci,2011,879(23):2315-2322.
- [19]GIORGI M A,COHEN ARAZI H,GONZALEZ C D,et al.Beyond efficacy:pharmacokinetic differences be-tween clopidogrel,prasugrel and ticagrelor[J].Expert Opin Pharmacother,2011,12(8):1285-1295.
- [20]TENG R,OLIVER S,HAYES M A,et al.Absorption,distribution,metabolism,and excretion of ticagrelor in healthy subjects[J].Drug Metab Dispos,2010,38(9):1514-1521.
- [21]WALLENTIN L,JAMES S,STOREY R F,et al.Effect of CYP2C19and ABCB1single nucleotide polymor-phisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes:a genetic substudy of the PLATO trial[J].Lancet,2010,376(9749):1320-1328.
- [22]STOREY R F,ANGIOLILLO D J,PATIL S B,et al.In-hibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syn-dromes:the PLATO(PLATelet inhibition and patient Outcomes)PLATELET substudy[J].J Am Coll Cardi-ol,2010,56(18):1456-1462.