氯吡格雷个体差异的遗传药理学研究进展

ChinJClinPharmacol701Vol26No9September2010(SerialNo131)Review氯吡格雷个体差异的遗传药理学研究进展Progressineffectsofpharmacogeneticsfactorsontheclopidogrelindividualvariation:2010-05-10:2010-07-23:(1986-),,,:,,Te:l(0512)67780040E-mai:lmiaolysuzhou@163com丁肖梁,谬丽燕(,215006)DINGXiao-liang,MIAOLi-yan(DepartmentofClinicalPharmacology,TheFirstAffiliatedHospitalofSoochowUniversity,Suzhou215006,JiangsuProvince,China):,,,,,:;;:R5411;R9726:A:1001-6821(2010)09-0701-06Abstract:clopidogrelisoneofthemostcommonlyusedantiplateletagentButitshowssignificantresponsevariabilityduringeffectiveantiplatelettherapyInordertoenhancetheefficacyandtoreducecardiovascularadverseeventsofclopidogre,ltheclinicianspaymoreattentiontoknowaboutthefactorsthatmaycauseclopidogrelresistanceThisarticlesummarizestheinfluenceofgeneticsfactorsonpharmacokineticsandpharmacodynamicsofclopidigrelinordertoprovidesomesuggestionsforpersonalizedmedicineKeyword:clopidogre;lgenepolymorphism;acutecoronarysyndrome,(acutecoronarysyndrome,ACS)(percutaneouscoronaryintervention,PCI),,,PCI[1],,,1998;,;2001P2Y12(AZD6140);,,;,,,[2],5%~30%,702中国临床药理学杂志26920109(131)[3],,,,,,1(ADP),,,,P450ADP(P2Y12),ADP,(cAMP)E1(PGE1)(VASP),(GPb/a),;(P-selectin),[4]2,,,,,ABCB1,,P(P-glycoprotein)[5],92%1[6];,P450,;1A22B62C19,;P4502,;2B62C92C193A[7,8]ABCB1P45021(ABCB1)Taubert[5],Caco-2,P-(P-gp)P-gp(mutidurgresistance,MDR)ATPP-gp,,P-gp,,,P-gpABCB121G2677T/A26C3435T12C1236T,,3[9]Hoffmeyer[10],3435TTP-gp,51%,3435T,Sakaeda[11],3435T,ABCB1,ABCB1Taubert[5]ABCB1Caco-2P-gp,P-gpPCI,300,600,900mg,C3435T,300mg600mg,3435TT(CmaxAUC),CTTT4h,,CCCT,300mg600mg,;900mg,TT,,ABCB1C3435TSpiewak[12]ABCB1,C3435T;PAPI[13],3435CTC3435TP-gp,,ABCB1C3435TG2677T/AC1236TChinJClinPharmacol703Vol26No9September2010(SerialNo131)22(P450)221CYP2C19,CYP,CYP2C19,CYP2C1925,10CYP2C19*2CYP2C19*3,CYP2C19*172C19,[14]Brandt[15],300mg,20%,;,,CYP2C19*2(722%vs278%,P=003),CYP2C19*2,[Cmaxwt/wtvswt/*2vs*2/*2:(584!92)vs(353!43)vs279ng∀mL-1,P=002][16,17],CYP2C19*2*3,,,,,*2*3Mega[18],CYP2C19*2,,Hulot[19],2C19*2,,,CYP2C19*2Giusti[20]1419PCI,,,2C19*2,,2C19*2Geisler[21]237PCI,600mg6h,,2C19*2,(*2vs*1/*1:OR:46,95%CL:25~87,P0001),Logistic,*2(OR:371,95%CL:187~735)(OR:1072,95%CL:256~4488),,*17PAPI[13],2C19*212%,,10%,[22],600mg,ADP14%,30,,6[23]2C19,1,,2C19*2,,14%(:624%vs433%,P0001;OR:218,95%CL:160~297;:413%vs225%,P0001;OR:243,95%CL:174~338),,14%,1(60%vs20%,HR:30,95%CL:14~68,P=0004)[13,15-18,24],CYP2C19,CYP2C19FDA,(),;,:2C19[25]CYP2C19*2*32C192,,,222CYP3A4/52C92B61A2Clarke[26],CYP3A4/5,CYP3A4/5Lau[27],3A4,[28],Lau[29],,CYP3A4Angiolillo[30],CYP3A4IVS10+12GA,Suh[31]704中国临床药理学杂志26920109(131),3A5*3,,;,3A4(),3A5,3A5*3,3A4/5,,;[15,18-21,32,33],CYP2C92B61A2Brandt[15],2C9*2*3,[wt/wtwt/*2vs*2/*2*3:(579!89)vs(340!54)ng∀mL-1,P=0006),[30][34],CYP2C19*2,2C9*3,,Mega[18],CYP2B6,,[15,19][15,18,19],CYP1A2CYP3A3A43A5,CYP3A50%~60%3A4,3A4;3A5*3,,3A5*370%3A5*33###P2Y12,,;,,,,ADPP2Y12,ADP,P2Y12,Fontana[35],P2Y1222(G52TC34T),3(-C139T-T744C-ins801A)4(-C139T-T744C-ins801AG52T),H1()H2(),862%138%H2,ADP,cAMP[36],P2Y12,,H2(30%vs21%)H2,Hetherington[37],P2Y12,;744,,G,200,P2Y12,Male[38],;,P2Y12744CCYP2C19*2,;P2Y12T744C,P2Y12CD61CD62(P-),,[20,39]P2Y12C34T,P2Y12mRNA[35],P2Y12,,4,;,,,(),,:[1]SmithSCJr,AllenJ,BlairSN,etal.AHA/ACCguidelinesforsecondarypreventionforpatientswithcoronaryandotheratheroscleChinJClinPharmacol705Vol26No9September2010(SerialNo131)roticvasculardisease:2006updateendorsedbytheNationalHeart,Lung,andBloodInstitute[J].JAmCollCardiol,2006;47:2130-2139.[2]SerebruanyVL,SteinhublSR,BergerPB,etal.Variabilityinplateletresponsivenesstoclopidogrelamong544individuals[J].JAmCollCardiol,2005;45:246-251.[3]MatetzkyS,ShenkmanB,GuetteV,etal.Clopidogrelresistanceisassociationwithincreasedriskofrecurrentatherothrombpticeventsinpatientwithacutemyocardialinfarction[J].Circulation,2004;109:3171-3175.[4]HollopeterG,JantzenHM,VincentD,etal.IdentificationoftheplateletADPreceptortargetedbyantithromboticdrugs[J].Nature,2001;409:202-207.[5]TaubertD,vonBeckerathN,GrimberyG,etal.ImpactofP-glycoproteinonclopidogrelabsorption[J].ClinPharmacol,2006;80:486-501.[6]TangM,MadhuM,YangJ,etal.Antiplateletagentsaspirinandclopidogrelarehydrolyzedbydistinctcarboxylesterases,andclopidogrelistransesterificatedinthepresenceofethylalcohol[J].JPharmacolExperTher,2006;319:1467-1476.[7]KazuiM,NishiyaY,IshizukaT,etal.IdentificationofthehumancytochromeP450enzymesinvolvedinthetwooxidativestepsinthebioactivationofclopidogreltoitspharmacologicallyactivemetabolite[J].DrugMetabDispos,2010;38:92-99.[8]HagiharaK,KazuiM,KuriharaA,etal.Apossiblemechanismforthedifferencesinefficiencyandvariabilityofactivemetaboliteformationfromthienopyridineantiplateletagents,prasugrelandclopidogrel[J].DrugMetabDispos,2009;37:2145-2152.[9]TangK,NgoiSM,GweePC,etal.DistincthaplotypeprofilesandstronglinkagedisequilibriumattheMDR1multidrugtransportergenelocusinthreeethnicAsianpopulation[J].Pharmacogenetics,2002;12:437-450.[10]HoffmeyerS,BurkO,vonRichterO,etal.Functionalpolymorphismsofthehumanmultidrug-resistancegene:multiplesequencevariationsandcorrelationofoneall