药物基因学及临床应用课件

藉药物基因学检测决定华法令的用药剂量

Warfarin

Pharmacogenomics常敏之医师荣民总医院心脏科阳明大学心脏血管研究中心榮民總醫院Anti-coagulants

WafarinHeparinLMWH

Fondaparinux

Bivalirudin

Rivaroxaban

AntithrombinIIIProteinCProteinSTissuefactorpathwayinhibitor凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ、维他命K和华法令肝细胞制造凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ蛋白质炼上的麸氨酸须经r-carboxylation。必须维他命K。维他命K华法令华法令的临床用途

静脉血栓肺栓塞房颤瓣膜置换术Warfarin临床使用华法令急诊最常见的药害:1.胰岛素2.华法令华法令的有效且安全的范围很窄，且个体所须剂量的差异极大。须藉一连串检测血液的凝血酵素原时间（INR），才足以调整达到最终的治疗剂量

药效学(PD)和药物动力学(PK)Drugmetabolizingenzymes(DME):Prodrugs=>activedrugs(Codeine/Morphine)Activedrugs=>inactivecompounds(warfarin)DrugtransportersInfluenceintracellulardrugconcentrations;muchlesswell-studied药物动力学(PK)药物分解代谢酵素PhaseI:Oxidation,reduction,hydrolysisPhaseII:Attachotherchemicalentities:acetylation,glucuronidation,sulfation,methylationPharmacogenomics:TranslatingFunctionalGenomicsintoRationalTherapeutics.EvansandRellingScience1999华法令相关的29类基因VKOR基因&CYP2C9基因VitaminKepoxide

reductasecomplex,subunit1(VKOR)CytochromeP450,family2,subfamilyC,polypeptide9(CYP2C9)II,VII,IX,XII,VII,IX,XSicklecellanemiaCAG→CTG(Glu

→Val)Polymorphism:allele>1%

基因突变与多形性基因突变与多形性对偶基因

基因型CYP2C9

&VKOR对偶基因VKOR对偶基因:-1639G或-1639ACYP2C9对偶基因:CYP2C9*1(wild),CYP2C9*2,CYP2C9*3CYP2C9VKORII,VII,IX,XII,VII,IX,X华法令用量:东西方人不同EthnicityWarfarindoseReferencesAsian

Chinese3.3(mg/day)Q.J.Med.89,127-135Japanese3.3(mg/day)Clin.Pharmacol.Ther.63,519-528Caucasian

American5.1(mg/day)JAMA,287,1690-1698.Italian5.5(mg/day)Blood,105,645-649.“Geneticspointsthegunbutenviromentpullsthetrigger!”VKORC1&CYP2C9对偶基因的差异VKORC1(-1639) CYP2C9G A *1 *2 *39% 91% 95% 0% 5%63% 37% 70% 20% 10%中国人西方人

VKORC1&CYP2C9基因型东西方差异VKORC1基因型与华法令用量aPvalueofcomparisonbetweenAAandAG+GGgroups.P-value<0.0001usingTtest.Datarepresentmean±SD.VKORC1起动子-1639位点出现G或A的多型性。-1639AA基因型所需华法令的维持剂量远低于-1639AG或-1639GG基因型所需的剂量。VKORC1启动子活性:G,A不同VKORC1-1639AhaslessVKORC1promoteractivityandlessVKORC1E-boxconsensus:CANNTGHypothesis:-1639A>GabolishtheEbox

CAGGTG(E-box)CGGGTG(E-boxabolished)Clin

Pharmacol

Ther2008Jul;84(1):83-9.荣总、台大、长庚、高医大、新光医院中央研究院生物医学研究所108病人VKORC1和CYP2C9快速定型VKORC1-1639G>AGGGGGGAGAGAGAAAAAACYP2C9*1/*1*1/*3*3/*3*1/*1*1/*3*3/*3*1/*1*1/*3*3/*3StartingDose(mg)53.753.753.752.52.52.51.251.25PTINR(2-3);华法令调剂量

1周2周4周、8周、12周、6月随访PTINR(2-3);华法令调剂量

PTINR(2-3);华法令调剂量前瞻性试验Clin

Pharmacol

Ther2008Jul;84(1):83-9.1周1周1周VKORC1-1639G>ACYP2C9StartingDose(mg/d)Frequencyn(%)DoseMatchn(%)GG*1/*153(2.8%)2(66.7%)GG*1/*33.7500GG*3/*33.7500AG*1/*13.7517(15.7%)12(70.5%)AG*1/*32.51(0.9%)1(100%)AG*3/*32.500AA*1/*12.583(76.9%)58(69.9%)AA*1/*31.254(3.7%)2(50%)AA*3/*31.2500Totaln(%)108(100%)74(68.5%)第12周随访华法令的用量分析第12周随访华法令的用量分析结果83％的病患在华法令治疗2周内就可达到血中稳定的治疗INR值。在治疗第4周可达到90%。治疗第12周，华法令的平均剂量2.760.88mg(1~6mg)。。74/108(69%)预测值与实际值吻合基因检测对于低(1mg)或高剂量(5mg)组特别有帮助基因检测对低或高剂量华法令组有帮助NEJM2009;360:753-64回归分析Dose=-0.432+0.769xpredictdose-0.015xAge+1.125xBSADosealgorithm:Thesefactorsinthismodelaccountedfor48%.R2=0.482

WarfarinSensitivityTestCYP2C9:PolymorphismsproducedefectiveCYP2C9proteinthatreducemetabolismofwarfarin,thusmoresensitivetowarfarinVKORC1(vitamin

Kepoxide

reductasecomplexsubunit

1):warfarininhibitsVKORC1,andhaplotypesassociatedwithchangeinactivityandwarfarindoseVerigene®(NanosphereInc.)FDAClearsGeneticLabTestforWarfarinSensitivity

TheU.S.FoodandDrugAdministrationtodayclearedformarketinganewgenetictestthatwillhelpphysiciansassesswhetherapatientmaybeespeciallysensitivetotheblood-thinningdrugwarfarin(Coumadin),whichisusedtopreventpotentiallyfatalclotsinbloodvessels.One-thirdofpatientsreceivingwarfarinmetabolizeitquitedifferentlythanexpectedandexperienceahigherriskofbleeding.Researchhasshownthatsomeoftheunexpectedresponsetowarfarindependson

variantsoftwogenes,CYP2C9andVKORC1.TheNanosphere

Verigene

WarfarinMetabolismNucleicAcidTestdetectssomevariantsofbothgenes."Today’sactionoffersphysicians

thefirstFDAclearedgenetictestforwarfarinsensitivity,whichisanotherstepinourcommitmenttopersonalizedmedicine,”saidDanielSchultz,M.D.,director,FDA’sCenterforDevicesandRadiologicalHealth.“Withthistest,physiciansmaybeabletousegeneticinformationalongwithotherclinicalinformationtotreattheirpatients.”Warfarinisthesecondmostcommondrug,afterinsulin,implicatedinemergencyroomvisitsforadversedrugevents.FORIMMEDIATERELEASE

September17,2007

个人化医学IfitwerenotforthegreatvariabilityamongIndividuals,medicinemightaswellbeascienceandnotanart. -SirWilliamOsler,1892

结论华法令的有效且安全的范围很窄，须反复检测血液的INR，以达到最终适合的治疗剂量华法令在体内的药理作用深受VKORC1和CYP2C9两种酵素的影响VKORC1-1639G或A的多形性，影响VKORC1酵素的生成量。-1639