抗癫痫药遗传药理学研究进展ppt课件.ppt

抗抗癫痫药遗传药理学研究理学研究进展展2024/5/26 周日周日1.DifferentialdrugefficacyDifferentialdrugefficacySamesymptomsSamefindingsSamedisease(?)SameDrug.DifferentEffects?GeneticDifferencesPossibleReasons:Non-ComplianceDrug-druginteractionsChanceOr.2024/5/26 周日周日2.PolymorphismsAffectDrugHandlingPolymorphismsAffectDrugHandlingandDrugTargetsandDrugTargetsGeneticPolymorphismPharmacokineticsPharmacokineticsPharmacodynamicsPharmacodynamicslReceptorslIonChannelslEnzymeslMetabolismlTransporterslProteinBinding2024/5/26 周日周日3.NormalPopulationDistribution.10500101520Enzymeactivities,Units/mlPercentofsubjectsper0.5Units/mlofactivity2024/5/26 周日周日4.Geneticpolymorphismofdrugmetabolizingenzymes.105005101520Enzymeactivities,Units/mlPercentofsubjectsper0.5Units/mlofactivitySlightadverseeffectsSevereadverseeffects2024/5/26 周日周日5.ProductFunctionMDR1/ABCB1P-glycoproteinTransmembranetransportSCN1A1subunitsodiumchannelMovementofsodiumionscrossmembraneGABBR1Gamma-aminobutyricacidreceptorBMembranereceptorGABA-BTNFSubunitoftumournecrosisfactorAssociatedwiththeinflammatorypathwayHLAHLAAssociatedwithimmuneresponse.CYP3ACytochromep450enzymeAssociatedwithhydroxylationCYP2C19Cytochromep450enzymeAssociatedwithhydroxylationCYP2C9Cytochromep450enzymeOmegaoxidationpathwayCYP2A6Cytochromep450enzymeAssociatedwithoxidationMRPMultidrugresistance-associatedproteinTransmembranetransportOCTN2OrganiccationtransportproteinTransmembranetransportUGT1A6UridinediphosphateglycosyltransferaseAssociatedwithglucuronidationpathwayCYP1A2Cytochromep450enzymeAssociatedwithhydroxylationCYP2D6Cytochromep450enzymeAssociatedwithhydroxylationCYP2C8Cytochromep450enzymeAssociatedwithhydroxylationPXRPregnaneXreceptorAssociatedwithindirectmetabolisminhydroxylationpathwayPRNPCellularprionproteinAssociatedwithneuronprotectionCanditatedGenesassociatedwithpharmacogeneticsofantiepilepticdrugs2024/5/26 周日周日6.DrugtransportersDrugtransporters2024/5/26 周日周日7.pharmacogenetics40%-50%Drug-resistanceEpilepsy2024/5/26 周日周日8.ModeloftheproposedroleofcellspecificMDR1expressioninepilepticbrain2024/5/26 周日周日9.ImmunohistochemicaldetectionofMDR1expressioninhumandrug-refractoryepilepticbrain.BMCMed.2004;2:37MDR1expressionanddrug-resistanceepilepsy2024/5/26 周日周日10.C3435TSchematicrepresentationofthemultidrugresistance-1(MDR1)geneandputativeproteinsecondarystructure.MDR1polymorphismanddrug-resistanceepilepsy2024/5/26 周日周日11.NEnglJMed2003;348:1442-8.SummaryofGenotypeandPhenotypeDataTotalPhenotypeNo.MDR13435GenotypeCCCTTTno.(%)Drug-resistantepilepsy20055(27.5)106(53.0)39(19.5)Drug-responsiveepilepsy11518(15.7)63(54.8)34(29.6)Control20037(18.5)116(58.0)47(23.5Forall315patientswithepilepsy,patientswithdrug-resistantepilepsyweremorelikelythanthosewithdrug-responsiveepilepsytohavetheCCgenotypethantheTTgenotype(x2=7.65,P=0.006).MDR1polymorphismanddrug-resistanceepilepsy2024/5/26 周日周日12.CompoundsTimeWild-TypeS467CMutantminl/mgproteinL-3HCarnitine3884.213.94(100)102.81.20(9.9)*3HAcetyl-carnitine5597.87.60(100)103.95.38(13.5)*14CTEA303046.50.99(100)48.11.30(104.8)3HPyrilamine5993.59.95(100)873.94.42(75.0)*3HQuinidine51524.523.30(100)1446.521.20(84.3)3HVerapamil52539.936.43(100)2540.136.81(103.0)*Significantlydifferentfromtheuptakebywild-typeOCTN2byStudentsttest(p0.05).UptakeofcarnitineandorganiccationsbyHEK293cellsexpressingwild-typeandS467C-mutantOCTN2Pharmacology2002,302:1286-12942024/5/26 周日周日13.VerapamilStartedJan03DateofHospitalizationDaysSincePriorHospitalizationUseofVerapamilasaPetentialP-GlycoproteinInhibitorinaPatientWithRefractorEpilepsyTheAnnalsofPharmacotherapy2004,38:1631-42024/5/26 周日周日14.DrugmetabolismDrugmetabolism2024/5/26 周日周日15.EnzymesassociatedwithmajormetabolicpathwaysCarbamazepineCYP3A4,CYP1A2,CYP2A6,CYP2C8,CYP2C19,CYP2D6,UGT1A6,UBG2BValproicacid50%byUGT,CYP2C9,CYP2C19PhenytoinCYP2C9,CYP2C19,UGTPhenobarbitalCYP2C9,CYP2C19PrimidoneCYP2C9,CYP2C19,Gabapentin95%excretedunchangedbykidney,restbytransaminaseandvitaminB6TiagabineCYP3A4,UGTTopiramate80%excretedunchangedbykidney,restCYP2C9,CYP2C19FelbamateCYP2E1,CYP3A4,CYP2C19LamotrigineMorethan70%UGT1A4,10%excretedunchanged*AlterationinanyenzymeimportantinmetabolismcanalterthemetabolitepopulationformedaffectingefficacyandadverseeventprofileEnzymesassociatedwithmajormetabolicpathways*2024/5/26 周日周日16.Genotypen(%)Meandose(mgdd)Meanoncentration(range)(mg/l)(range)Total6025315.7CYP2C9*1/*137(62%)287(75425)15.8(2.236.4)CYP2C9*1/*29(15%)201(150225)*16.1(9.031.2)CYP2C9*1/*39(15%)196(150275)*13.8(5.118.2)CYP2C9*2/*32(3%)175(150200)*20.4(12.827.9)CYP2C9*2/*23(5%)217(175275)*14.0(10.617.6)*P0.01versusCYP2C9*1/*1CYP2C9genotypedistributionandmeanphenytoinmaintenanceDose/meanphenytoinsteady-stateserumconcentrationperenotypePharmacogenetics2001,11:287-2912024/5/26 周日周日17.Genotypen(%)Meandose(mgdd)(range)Total36260CYP2C9*1/*119(53%)314(200425)CYP2C9*1/*26(17%)193(150225)*CYP2C9*1/*37(19%)202(150275)*CYP2C9*2/*31(3%)150*CYP2C9*2/*23(8%)217(175275)*PAgenotypePNAS2005,102:5507-122024/5/26 周日周日30.ImmunogeneticbackgroundImmunogeneticbackground2024/5/26 周日周日31.Carbamazepine-inducedStevensJohnsonSyndrome(SJS)andHLA-B*1502PharmacogeneticsandGenomics2006,16:2973062024/5/26 周日周日32.PharmacogeneticsandGenomics2006,16:297306Carbamazepine-inducedStevensJohnsonSyndrome(SJS)andHLA-B*15022024/5/26 周日周日33.2024/5/26 周日周日34.l后面内容直接后面内容直接删除就行除就行l资料可以料可以编辑修改使用修改使用l资料可以料可以编辑修改使用修改使用l资料料仅供参考，供参考，实际情况情况实际分析分析2024/5/26 周日周日35.l感感谢您的您的观看和下看和下载lThe user can demonstrate on a projector or computer,or print the presentation and make it into a film to be used in a wider field2024/5/26 周日周日36.