药物转运体的遗传药理学-transporter

PharmacogeneticsofDrugTransportersWeiZhangPharmacogeneticsResearchInstituteInstituteofClinicalPharmacologyCentralSouthUniversityIntroductionDrugtransporterAbsorptionDistributionMetabolismExcretionMajordrugtransportersexpressedintheliver,kidney,smallintestineandbrainMRP2Oatp1,2,4/OATP-C,B,8OCT1NTCPBSEPMRP2P-gp/MDR1【SmallIntestine】【Bloodbrainbarrier】【Liver】【Kidney】BiliaryExcretionUrinaryexcretionOAT2PEPT1ASBTPepT2OCTN1,2MRP2,4OAT1OCT2BloodOAT3MRP3BCRPMRP3OATPsOATPsAbsorptionOAT4BCRPMrp1BcrpOat3Oatp2/OATP-AOatp2/OATP-APepT2Oat3/OAT3Oatp3/OATP-AOatp2/OATP-ACSF【Blood-CSFBarrier】BloodMrp1P-gp/MDR1P-gp/MDR1P-gp/MDR1OrgandistributionImportanceofvectorialtransport,,(.ClassName(genenomenclature)ABCtransportersP-glycoprotein[P-gp]/multi-drugresistance1[MDR1/ABCB1],Multi-drugresistance-associatedprotein2[MRP2/ABCC2]Breastcancer-resistanceprotein[BCRP/ABCG2]Organicanion-transportingpolypeptidefamilyOATP1A2[OATP-A]/SLCO1A2OATP1B1[OATP-C]/SLCO1B1OATP1B3[OATP8]/SLCO1B3OATP2B1[OATP-B]/SLCO2B1OrganicaniontransporterfamilyOAT1/SLC22A6OAT2/SLC22A7OAT3/SLC22A8OrganiccationtransporterfamilyOCT1/SLC22A1OCT2/SLC22A2Generalfeatures1.Localizationinhumantissuesandbasicfunction（1）P-gp/MDR1(ABCB1)Localizationsmallandlargeintestines，adrenalgland，placental，kidney，liver，pancreas，brain，testesFunctionintothebile;intothegutlumen;intotheurine;blockingthetransferofxenobioticsacrossthehumanplacenta;preventingtheentryofsubstratesintotheCNS；（2）MRPs(ABCCproteins)Localizationintestines，kidney，liverFunctionbiliaryexcretion,intestinalexcretionandurinaryexcretionofthesubstrates（3）BCRP(ABCG2protein)Localizationintestines，placental，kidney，liverFunctionregulationofintestinalabsorptionandbiliarysecretionofsubstrates,andprotectionofthefetusandbrainfromtoxicxenobiotics.（4）OATP1A2(OATP-A)LocalizationLiver,brain,lung,kidneyandtestesFunctionplayapossibleroleinfexofenadineabsorptionfromtheintestine（5）OATP1B1(OATP-C)and-3(OATP8)Localizationliver-specifictissuedistributionFunctionuptakeofsubstratesfromthebloodintohepatocytes（6）OATP2B1(OATP-B)LocalizationLiver,brain,lung,kidney,placenta,heart,intestineandtestisFunctionNotwelldetermined（7）OAT1and-3LocalizationKidney(proximaltubules)Functionthekeymoleculesinrenalexcretion,responsibleforantibiotic-orantiviral-relatednephrotoxicity;OAT3isalsolocalisedontheblood–CSFbarrier.（8）OCT1、2、3OCT1basolateralmembraneofhepatocytes;playafundamentalroleintheuptakeofsubstratesintotheliver；OCT2kidney;ThemajortransporterfortheuptakeofmanycationsfromthebloodsidesintorenalepithelialcellsOCT3Aorta,skeletalmuscle,prostate,salivarygland,adrenalgland,placenta;Thefunctionwasnotwelldetermined.SubstratesSubstratesSubstratesSitesofpolymorphismsandallelicfrequencyindifferentethnicpopulationsPolymorphismofMDR1PolymorphismofMRP2PolymorphismofBCRPPolymorphismofOATP1A2NDinAsiansPolymorphismofOATP1B10.02/0.04PolymorphismofOATP1B3PolymorphismofOAT1ExtremelylowPolymorphismofOCT1PolymorphismofOCT2Impactofpolymorphismsonpharmacotherapy1.PharmacogeneticsstudyofMDR1ProcNatlAcadSci.2000;28;97(7):3473-8.MDR-1proteinexpressionAUCCmaxThefirstreportonMDR1C3435TpolymorphismMDR13435CTaffectsmRNAstabilityPharmacogeneticsandGenomics2005,15:693–704Time(hours)0102030405060Plasmatalinolol(ngml-1)0100200300400P=0.455(ANOVA)genotype0100200300400500GG/CCTT/TTGT/CTAT/CTP=0.011P=0.004AUC(0-Cmax)TalinololAbsorptionZWXetal.2004ABCB1C3435TgenotypeAssociatedwithAldosteronesysteminkidneyPharmacogeneticsandGenomics2007,17:137–144AIDStherapyWithRegardstoMDR-1PolymorphismFellayJetalLancet2002Haasetal,12thCROI,2005p=0.02CCCTTTTimetoFailureonEfavirenz(n=340)2.PharmacogeneticsstudyofOATP1B1OATP1B1polymorphismonpravastatinPK&PDsimvastatinacidPKandOATP1B1*17Pharmacogenetics&Genomics2006,16:873–879repaglinidenateglinideOATP1B1polymorphismonoralglucose-loweringdrugsPharmacogenetics&Genomics2006,16:683–691PharmacogeneticsofSLCO1B1haplotypesonirinotecandispositioninAsiancancerpatientsConclusionThepolymorphismofgenesencodingdrugtransportersisausefulmarkertointerpretlargeinterindividualdifferencesinthepharmacokineticsandresponse.Exceptforafewcases(e.g.,theSLCO1B1genotypeandstatinspharmacokinetics/pharmacodynamics),therearestilldiscrepanciesintheresultsoffunctionalconfirmationoftheSNPs.Thesubstratespecificityofmosttransportersisextremelybroadandshowssubstantialoverlapbetweendifferentmembersofthesuperfamily.Multiplegeneanalysisofthenetworkofgenesinvolvedindrugmetabolism,transport,andresponse(e.g.,receptors),ispreferable.Thankyou!Exon26DifferencebetweenBCRPandotherABCtransporters:2nucleotide-bindingdomains(NBD)and12transmembranedomains(TMD)asingleNBDattheaminoterminusfollowedby6TMDsHalf-transporter?Homodimer?Homotetramer!J.Biol.Chem.(2004)Int.J.Cancer(2002)C3435TVariationisAssociatedwithDecreasedDigoxinAbsorptionCC(n=5)CT(n=4)TT(n=6)AUC0-4h(ngh/ml)4.11±0.573.20±0.49*3.27±0.58*AUC0-24h(ngh/ml)8.84±3.285.8±1.945.74±3.04Sakaedaetal.Pharm.Res.18:1400-1404,2001*StatisticallydifferentcomparedtoCC,p0.05ABCB13435CCGenotypeAssociatedwithEpilepsyDrugResistantnCCCTTTDrugResistant200