CYP2C19基因多态性对药物代谢的影响及其个体化用药

CN341206/R,ISSN10092501Email:[e-mail]2010Aug;15(8):949-95320100721收稿20100821修回严非,男,硕士研究生,研究方向为临床药理学Email:[e-mail]熊玉卿,通信作者,女,教授,博士生导师,研究方向为临床药理学与药物代谢动力学Tel:07916361081Email:[e-mail]2C19基因多态性对药物代谢的影响及其个体化用药严非,夏春华,熊玉卿南昌大学医学院临床药理研究所,南昌330006,江西CYP2C19是一种重要的药物代谢酶,参与多种药物的体内代谢该酶的活性在不同个体和种族之间存在着显著的差异本文综述了CYP2C19酶的基因多态性对药物代谢的影响,以期为指导临床合理用药打下坚实的理论基础,确保临床用药的安全性和有效性,真正的实现个体化用药CYP2C19;基因多态性;药物代谢;个体化用药:R969:A:10092501(2010)08094905P450,CYP2C19CYP450,,2%CYP2C19,,[1-2]CYP2C191CYP2C19CYP2C19S,14,182CYP2C19m1(CYP2C19*2)[3]CYP2C19m2(CYP2C19*3)[4]5(GA)M1,CYP2C19m1,CYP2C194636,(GA)M2,CYP2C19m22CYP2C19,CYP2C19,CYP2C19*17[5],CYP2C9*17CYP2C19*1,CYP2C19*17EMCYP2C19CYP2C19,(extensivemetabolizer,EM)(poormetabolizer,PM)CYP2C19*2CYP2C19*399%88%M1PMCYP2C19,PMPM3%~5%,,,!949!PM13%~23%[6-7](),PM[8]CYP2C19,,CYP2C19,CYP2C191[9]1CYP2C19(%)CYP2C19*219154GA80160CT80161AG,I331V7~329~1313CYP2C19*317948GA80161AG87313ACW212X,I331V0~700CYP2C19*41AG80161AGGTG,I331V001CYP2C19*590033CTR433W080CYP2C19*612748GA80161AGR132Q,I331V050CYP2C19*812711TCTrp120A0110CYP2C19*17-806CT80161AGI331V416~1917~192CYP2C19CYP2C19:[10][11][12][13][14]CYP2C19,,EM(W),,PM(M),EM,PMCYP2C192.1CYP2C19,,CYP2C19[15-16]70%~90%CYP2C9[17],CYP2C19,CYP2C19,CYP2C9CYP2C19CYP2C19[18]CYP2C19:219CYP2C19*1/*1,1CYP2C19*2/*2,11CYP2C19*1/*2CYP2C19*1/*3W()M()[19]W3.258mg/L,(3.8∀2.8)mg/L,M4.215mg/L,(4.8∀2.9)mg/L24PMM19,WM,PM,,!950!ChinJClinPharmacolTher2010Aug;15(8)2.2P450CYP2C19CYP3A4,,CYP2C19CYP3A4,CYP2C195,PMCYP2C19,PM,[20-21]PMAUC,CYP2C19[22]20mg20mg,EMPM,CYP2C192.3,CYP2C19,CYP3A4CYP2D6,CYP2C19[23],[24]CYP2C19:PCR,2320EM(EM10,10),3PM20mg,PMCmaxAUC0-tAUC0-#EM,PMt1/2EM,EMCmaxAUC0-tAUC0-#Herrlin[25],PM,2.4,CYP2C19,InomataS[26]:PCR,6320EM(EM),14PMPMAUC0-24EM,EMCYP2C19,CYP2C193CYP2C19,∃%,&Science∋,[27-28],,,CYP2C19,,,51,PCRCYP2C19,2229(),,4(),24,19CYP2C19,1916,,CYP2C19,,[29],,,,[1]PestkaEL,HaleAM,JohnsonBL,eta1.CytochromeP450testingforbetterpsychiatriccare[J].!951!2010Aug;15(8)JPsychosocNursMentHealthServ,2007,45(10):15-18.[2]BertilssonL.MetabolismofantidepressantandneurolepticDurgsbycytochromep450:clinicalandinterethnicaspects[J].ClinPharmacolTher,2007,82(5):606-609.[3]DeMoraisSM,WilkinsonGR,BlaisdellJ,eta1.ThemajorgeneticdefectresponsibleforthepolymorphismofSmephenytoininhumans[J].JBiolChem,1994,269(22):15419-15422.[4]DeMoraisSM,WilkinsonGR,BlaisdellJ,eta1.IdentificationofanewgeneticdefectresponsibleforthepolymorphismofSmephenytoininJapanese[J].MolPharmacol,1994,46(4):594-598.[5]SimSC,RisingerC,DahlML,eta1.AcommonnovelCYP2C19genevariantcausesultrarapiddrugresponsetoprotonpumpinhibitorsandantidepressants[J].ClinPharmacolTher,2006,79(1):103-113.[6]OatesNS,ShahRR,IdleJR,eta1.Influenceofoxidationpolymorphismonphenforminkineticsanddynamics[J].ClinPharmacolTher,1993,34(6):827-834.[7]XiaoZS,GoldsteinJA,XieHG,eta1.DifferencesintheincidenceoftheCYP2C19polymorphismaffectingtheSmephenytoinphenotypeinChineseHanandidentificationofanewrareCYP2C19mutantallele[J].JPharmacolExperiTher,1997,281:604-609.[8],.CYP2C19[J].,2003,34(2):171-174.[9],.P450[J].,2008,31(3):206-212.[10]JiangDC,BaiXR,ZhangQX,eta1.EffectsofCYP2C19andCYP2C9genotypesonpharmacokineticvariabilityofvalproicacidinChineseepilepticpatients:nonlinearmixedeffectmodeling[J].EurJClinPharmacol2009,65(12):1187-1193.[11]HunfeldND,TouwDJ,MathotRA,eta1.AcomparisonoftheacidinhibitoryeffectsofesomeprazoleandpantoprazoleinrelationtopharmacokineticsandCYP2C19polymorphism[J].AlimentPharmacolTher,2010,31(1):150-159.[12]YuBN,ChenGL,HeN,eta1.PharmacokineticsofcitalopraminrelationtogeneticpolymorphismofCYP2C19[J].DrugMetabDispos,2003,31(10):1255-1259.[13]SimSC,NordinL,AnderssonTML,eta1.AssociationbetweenCYP2C19polymorphismanddepressivesymptoms[J].AmJMedGenetBNeuropsychiatrGenet,2010,153B(6):1160-1166.[14]ScholzL,OberwittlerH,RiedelKD,eta1.Pharmacokinetics,metabolismandbioavailabilityofthetriazoleantifungalagentvoriconazoleinrelationtoCYP2C19genotype[J].BrJClinPharmacol,2009,68(6):906-915.[15]WeberWW.Thelegacyofpharmacogeneticsandpotentialapplications[J].MutatRes,2001,479(1/2):1-18.[16],,,.CYP2C19[J].,2007,12(6):700-704.[17]KomatsuT,YamazakiH,AsahiS,eta1.Formationofadihydroxymetaboliteofphenytoininhumanlivermicrosomes/cytosol:rolesofcytochromesP4502C9,2C19,and3A4[J].DrugMetabDispos,2000,28(11):1361-1368.[18],,,.CYP2C19[J].,2004,13(10):922-925.[19],,,.CYP2C19[J].,2003,23(11):670-673.[20]ShiraiN,Furuta,MoriyamaY,eta1.EffectsofCYP2C19genotypicdifferencesinthemetabolismofomeprazoleandrabeprazoleonintragastricPH[J].AlimentPharmacolTher,2001,15(12):1929-1937.[21]SakaiT,AoyamaN,KitaT,eta1.CYP2C19genotpyeandpharmacokineticsofthreeprotonpumpinhibitorsinhealthysubjects[J].PharmRes,2001,18(6):721-727.[22],,,.CYP2C19[J].,2004,11(6):1002-1004.[23]SindrupSH,BrosenK,HansenMG,eta1.Pharmacokineticsofcitalopraminrelationtothesparteineandthemephenytoinoxidationpolymorphisms[J].TherDrugMonit,1993,15(1):11-17.[24],,,.CYP2C19[J].,2006,15(15):1296-1299.[25]HerrlinK,YasuiFurudoriN,TybringG,eta1.MetabolismofcitalopramenantiomersinCYP2C19/C