抗癫痫药遗传药理学研究进展

抗癫痫药遗传药理学研究进展DifferentialdrugefficacySamesymptomsSamefindingsSamedisease(?)SameDrug….DifferentEffects?GeneticDifferencesPossibleReasons:Non-Compliance…Drug-druginteractions…Chance…Or….PolymorphismsAffectDrugHandlingandDrugTargetsGeneticPolymorphismPharmacokineticsPharmacodynamicsReceptorsIonChannelsEnzymesMetabolismTransportersProteinBindingNormalPopulationDistribution.10500101520Enzymeactivities,Units/mlPercentofsubjectsper0.5Units/mlofactivityGeneticpolymorphismofdrugmetabolizingenzymes.105005101520Enzymeactivities,Units/mlPercentofsubjectsper0.5Units/mlofactivitySlightadverseeffectsSevereadverseeffectsProductFunctionMDR1/ABCB1P-glycoproteinTransmembranetransportSCN1Aα1subunitsodiumchannelMovementofsodiumionscrossmembraneGABBR1Gamma-aminobutyricacidreceptorBMembranereceptorGABA-BTNFαSubunitoftumournecrosisfactorAssociatedwiththeinflammatorypathwayHLAHLAAssociatedwithimmuneresponse.CYP3ACytochromep450enzymeAssociatedwithhydroxylationCYP2C19Cytochromep450enzymeAssociatedwithhydroxylationCYP2C9Cytochromep450enzymeOmegaoxidationpathwayCYP2A6Cytochromep450enzymeAssociatedwithoxidationMRPMultidrugresistance-associatedproteinTransmembranetransportOCTN2OrganiccationtransportproteinTransmembranetransportUGT1A6UridinediphosphateglycosyltransferaseAssociatedwithglucuronidationpathwayCYP1A2Cytochromep450enzymeAssociatedwithhydroxylationCYP2D6Cytochromep450enzymeAssociatedwithhydroxylationCYP2C8Cytochromep450enzymeAssociatedwithhydroxylationPXRPregnaneXreceptorAssociatedwithindirectmetabolisminhydroxylationpathwayPRNPCellularprionproteinAssociatedwithneuronprotectionCanditatedGenesassociatedwithpharmacogeneticsofantiepilepticdrugsDrugtransporterspharmacogenetics40%--50%Drug-resistanceEpilepsyModeloftheproposedroleofcellspecificMDR1expressioninepilepticbrainImmunohistochemicaldetectionofMDR1expressioninhumandrug-refractoryepilepticbrain.BMCMed.2004;2:37MDR1expressionanddrug-resistanceepilepsyC3435TSchematicrepresentationofthemultidrugresistance-1(MDR1)geneandputativeproteinsecondarystructure.MDR1polymorphismanddrug-resistanceepilepsyNEnglJMed2003;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-resistanceepilepsyCompoundsTimeWild-TypeS467CMutantminµl/mgproteinL-[3H]Carnitine3884.2±13.94(100)102.8±1.20(9.9)*[3H]Acetyl-carnitine5597.8±7.60(100)103.9±5.38(13.5)*[14C]TEA303046.5±0.99(100)48.1±1.30(104.8)[3H]Pyrilamine5993.5±9.95(100)873.9±4.42(75.0)*[3H]Quinidine51524.5±23.30(100)1446.5±21.20(84.3)[3H]Verapamil52539.9±36.43(100)2540.1±36.81(103.0)*Significantlydifferentfromtheuptakebywild-typeOCTN2byStudent'sttest(p0.05).UptakeofcarnitineandorganiccationsbyHEK293cellsexpressingwild-typeandS467C-mutantOCTN2Pharmacology2002,302:1286-12940306090120150Aug01Oct01Dec01Feb02Apr02Jun02Aug02Oct02Nov02Jan03Apr03VerapamilStartedJan03DateofHospitalizationDaysSincePriorHospitalizationUseofVerapamilasaPetentialP-GlycoproteinInhibitorinaPatientWithRefractorEpilepsyTheAnnalsofPharmacotherapy2004,38:1631-4DrugmetabolismEnzymesassociatedwithmajormetabolicpathwaysCarbamazepineCYP3A4,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*Genotypen(%)Meandose(mgdd)Meanoncentration(range)(mg/l)(range)Total6025315.7CYP2C9*1/*137(62%)287(75±425)15.8(2.2±36.4)CYP2C9*1/*29(15%)201(150±225)*16.1(9.0±31.2)CYP2C9*1/*39(15%)196(150±275)*13.8(5.1±18.2)CYP2C9*2/*32(3%)175(150±200)*20.4(12.8±27.9)CYP2C9*2/*23(5%)217(175±275)*14.0(10.6±17.6)*P0.01versusCYP2C9*1/*1CYP2C9genotypedistributionandmeanphenytoinmaintenanceDose/meanphenytoinsteady-stateserumconcentrationperenotypePharmacogenetics2001,11:287-291Genotypen(%)Meandose(mgdd)(range)Total36260CYP2C9*1/*119(53%)314(200±425)CYP2C9*1/*26(17%)193(150±225)*CYP2C9*1/*37(19%)202(150±275)*CYP2C9*2/*31(3%)150*CYP2C9*2/*23(8%)217(175±275)**P0.01versusCYP2C9*1/*1CYP2C9genotypeandmeanphenytoinmaintenancedosePharmacogenetics2001,11:287-291GroupCYP2C9CYP2C19No.Dose(mg/day/kg)Css(ug/ml)Css/doseG1*1/*1*1/*1523.58±1.486.6±4.81.7±0.8G2*1/*1*1/*2(47)643.50±1.339.1±7.32.3±1.2a*1/*3(17)G3*1/*1*2/*2(7)152.95±1.367.1±5.62.2±0.9*3/*3(3)*2/*3(5)G4*1/*3*1/*132.09±0.174.7±2.02.2±0.8*1/*2*1/*2*1,wild-typedalleleaComparedwithG1groupe,p=0.018.CYP2C9/19genotypes,thedailydosesandserum