ABCMdb

PMID: 20873966

Poguntke M, Hazai E, Fromm MF, Zolk O
Drug transport by breast cancer resistance protein.
Expert Opin Drug Metab Toxicol. 2010 Nov;6(11):1363-84. Epub 2010 Sep 27., [PubMed]

Sentences

No. Mutations Sentence Comment

34 ABCG2 p.Gln141Lys For example, the common ABCG2 421C>A (p.Gln141Lys; rs2231142) SNP causes reduced ABCG2 expression levels and altered substrate specificity, and has been associated with greater serum accumulation of orally administered ABCG2 substrates such as topotecan, diflomotecan and gefitinib [16-19]. Login to comment 75 ABCG2 p.Gln141Lys SulfasalazineTheABCG2c.421C>ASNPisassociatedwithincreased AUC(C/C,C/Avs.A/A:3.5-fold)andCmaxofa2000mg singledosesulfasalazine Pharmacogeneticassociationstudy:37healthyvolunteers[72] Rituximabplushyper-CVAD regimen(cyclophosphamide, vincristine,adriamycin, dexamethasone) ExpressionofABCG2inbonemarrowsamplesappeared associatedwithaworsePFSandlevelsofthisgene paralleledthestatusofminimalresidualdisease 20patientswithMCLenrolled intoaPhaseIIstudy [12] GefitinibTumorexpressionofABCG2wasassociatedwithacquired resistancetogefitinib,independentofEGFRmutations Casereport:1patientwithadvancedlungcancerand acquiredresistancetogefitinib [11] Gefitinib7(44%)of16patientsheterozygousforABCG2 c.421C>A(Q141K)developeddiarrheavsonly13(12%) of108patientshomozygousforthewild-typesequence (p=0.0046) Pharmacogeneticassociationstudy:129caucasianpatients withNSCLC [84] TopotecanElacridar (interaction) Completeapparentoralbioavailabilityoftopotecanwas observedwithco-administrationofelacridarbeforeor simultaneouslywith2mgoraltopotecan PhaseI,randomized,open-label,parallel-cohort, dose-findingstudyofelacridarandoral topotecan:20cancerpatients [15] RosuvastatinTheABCG2c.421C>Apolymorphismmayplayan importantroleinthepharmacokineticsofrosuvastatin (CCvsCA/AAgenotype:increasedAUCandCmax) Pharmacogeneticassociationstudy:14healthyChinese malevolunteerswhoareSLCO1B1521TTand CYP2C9*1/*1wild-typehomozygotes [85] FluvastatinSimvastatinAUC0--¥offluvastatinwas97or72%largerin participantswiththeABCG2c.421AAgenotypethanin thosewiththeCAorCCgenotype.TheAUC0--¥of simvastatinlactonewas111%largerinparticipantswith theAAgenotypethaninparticipantswiththeCC genotype.TheABCG2genotypehadnosignificanteffect onsimvastatinacidpharmacokinetics Pharmacogeneticassociationstudy:Inacrossoverdesign, 5healthyvolunteerswiththeABCG2c.421AAgenotype, 4withthe421CAgenotypeand23withthec.421CC genotypeingestedasingle40mgdoseoffluvastatin, pravastatinandsimvastatin,withawashoutperiodof 1week [67] TopotecanHeterozygousABCG2c.421CAalleleobservedin 2patientswasassociatedwitha1.34-foldincreasedoral bioavailabilityoftopotecancomparedtothebioavailability in10patientswiththewild-typeallele Pharmacogeneticassociationstudy:12patientswith ovarianorsmall-celllungcancer [16] ALL:Acutelymphoblasticleukemia;AML:Acutemyelogenousleukemia;MCL:Mantlecelllymphoma;NSCLC:Nonsmallcelllungcancer;PFS:Progression-freesurvival;P-gp:P-glycoprotein;SNP:Singlenucleotide polymorphism. Poguntke, Hazai, Fromm & Zolk Expert Opin. Drug Metab. Toxicol. Login to comment 78 ABCG2 p.Gln141Lys AMLinductionanthracycline ormitoxantroneincombination withcytarabine(insomecases additionalcytostaticdrugs) NodifferenceinABCG2mRNAexpressionbetween patientsrespondingtoinductiontreatmentand non-responders.Inthegroupofresponders,the 14patientswiththehighestexpressionhadsignificantly shorteroverallsurvival(mean38months)thanthe 14patientswiththelowestexpression Pharmacogeneticassociationstudy:40patientswithnewly diagnosedAML [86] TopotecanElacridar (interaction) Co-administrationoftheABCG2andP-gpinhibitor elacridarresultsinasignificantincreaseofthesystemic exposureoforaltopotecan:theapparentoral bioavailabilityincreasesfrom40to97.1%withoutand withelacridar,respectively Randomizedcontrolledtrial:CohortA:8patients randomizedtoreceiveoraltopotecanwithorwithout co-administrationofonesingleoraldoseof1000mg elacridar.CohortB:8otherpatientsrandomizedto receiveintravenoustopotecanwithorwithout1000mg oralelacridar [26] ClinicalevidenceagainstsignificantimpactofABCG2ondrugdispositionandeffect IrinotecanNosignificantchangesinirinotecanpharmacokinetics wereobservedinrelationtotheABCG2c.421C>A genotype Pharmacogeneticassociationstudy:88American Caucasians,94AfricanAmericans,938Africans,95Han Chinese,84Europeancaucasianpatientstreatedwith irinotecan [87] SulfasalazineNosignificantchangesinsulfasalazinepharmacokinetics wereobservedinrelationtotheABCG2c.421C>A genotype;pantoprazoleandfamotidinedidnotaffect sulfasalazinepharmacokineticsinanygenotypiccohort Pharmacogeneticassociationstudy,drug--druginteraction study:36malehealthyChinesesubjects [73] Taxaneandplatinum anticancerdrugs NoreproduciblesignificantassociationsbetweenABCG2 Q141Kgenotypeandoutcomeortoxicity Retrospectivepharmacogeneticanalysis:914ovarian cancerpatientsfromtheScottishRandomisedTrialin OvarianCancerPhaseIIItrial [88] PravastatinABCG2genotypeswerenotassociatedwithdifferencesin pravastatinpharmacokinetics Pharmacogeneticassociationstudy:107participants (69EuropeanAmericansand38AfricanAmericans) [63] IrinotecanCisplatinABCG2(c.34G>A,c.421C>A)SNPsdidnotcorrelate withirinotecan-PK,toxicity,tumorresponseandsurvival Pharmacogeneticassociationstudy:107patientswith advancedNSCLCtreatedwithirinotecanandcisplatin chemotherapies [89] LamivudineDispositionoflamivudinewasnotsignificantlyinfluenced byknowninvitrofunctionalvariantsofABCG2,Q141K, V12MandQ126X Pharmacogeneticassociationstudy:22healthymale Koreansubjects [90] ALL:Acutelymphoblasticleukemia;AML:Acutemyelogenousleukemia;MCL:Mantlecelllymphoma;NSCLC:Nonsmallcelllungcancer;PFS:Progression-freesurvival;P-gp:P-glycoprotein;SNP:Singlenucleotide polymorphism. Drug transport by breast cancer resistance protein 1368 Expert Opin. Drug Metab. Toxicol. Login to comment 391 ABCG2 p.Arg482Gly Multiple drugbinding sites on the R482G isoform of the ABCG2 transporter. Login to comment 529 ABCG2 p.Gln141Lys ABCG2 p.Val12Met The effect of ABCG2 V12M, Q141K and Poguntke, Hazai, Fromm & Zolk Expert Opin. Drug Metab. Toxicol. Login to comment 530 ABCG2 p.Gln126* (2010) 6(11) 1383 Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment