Breast Cancer Resistance Protein (ABCG2) in Clinic

1521-009X/43/4/490–509$25.00:490–509,April2015Copyrightª2015byTheAmericanSocietyforPharmacologyandExperimentalTherapeuticsMinireviewBreastCancerResistanceProtein(ABCG2)inClinicalPharmacokineticsandDrugInteractions:PracticalRecommendationsforClinicalVictimandPerpetratorDrug-DrugInteractionStudyDesignsCarolineA.Lee,1MeeghanA.O’Connor,TashaK.Ritchie,AleksandraGaletin,JackA.Cook,IsabelleRagueneau-Majlessi,HarmaEllens,BoFeng,MitchellE.Taub,MaryF.Paine,JosephW.Polli,JosephA.Ware,andMaciejJ.Zamek-GliszczynskiDrugMetabolismandPharmacokinetics,QPSLLC,ResearchTrianglePark,NorthCarolina(C.A.L.);DrugMetabolismandPharmacokinetics,BoehringerIngelheimPharmaceuticals,Inc.,Ridgefield,Connecticut(M.A.O.,M.E.T.);CentreforAppliedPharmacokineticResearch,ManchesterPharmacySchool,TheUniversityofManchester,Manchester,UnitedKingdom(A.G.);PharmacokineticsandDrugMetabolism(B.F.)andClinicalPharmacology,GlobalInnovativePharmaBusiness(J.A.C.),PfizerInc.,Groton,Connecticut;SchoolofPharmacy,UniversityofWashington,Seattle,Washington(I.R.-M.,T.K.R.);DrugMetabolismandPharmacokinetics,GlaxoSmithKline,ResearchTrianglePark,NorthCarolina(M.J.Z.-G.,J.W.P.)andKingofPrussia,Pennsylvania(H.E.);CollegeofPharmacy,WashingtonStateUniversity,Spokane,Washington(M.F.P.);andClinicalPharmacology,Genentech,SouthSanFrancisco,California(J.A.W.)ReceivedNovember16,2014;acceptedJanuary9,2015ABSTRACTBreastcancerresistanceprotein(BCRP;ABCG2)limitsintestinalabsorptionoflow-permeabilitysubstratedrugsandmediatesbiliaryexcretionofdrugsandmetabolites.BasedonclinicalevidenceofBCRP-mediateddrug-druginteractions(DDIs)andthec.421CAfunctionalpolymorphismaffectingdrugefficacyandsafety,boththeUSFoodandDrugAdministrationandEuropeanMedicinesAgencyrecommendpreclinicalevaluationand,whenappropriate,clinicalassessmentofBCRP-mediatedDDIs.AlthoughmanyBCRPsubstratesandinhibitorshavebeenidentifiedinvitro,clinicaltrans-lationhasbeenconfoundedbyoverlapwithothertransportersandmetabolicenzymes.RegulatoryrecommendationsforBCRP-mediatedclinicalDDIstudiesarechallenging,asconsensusislackingonthechoiceofthemostrobustandspecifichumanBCRPsubstratesandinhibitorsandoptimalstudydesign.Thisreviewproposesapathforwardbasedonacomprehensiveanalysisofavailabledata.Oralsulfasalazine(1000mg,immediate-releasetablet)isthebestavail-ableclinicalsubstrateforintestinalBCRP,oralrosuvastatin(20mg)forbothintestinalandhepaticBCRP,andintravenousrosuvastatin(4mg)forhepaticBCRP.Oralcurcumin(2000mg)andlapatinib(250mg)arethebestavailableclinicalBCRPinhibitors.Tointerro-gatetheworst-caseclinicalBCRPDDIscenario,studysubjectsharboringtheBCRPc.421C/Creferencegenotypearerecommended.Inaddition,ifsulfasalazineisselectedasthesubstrate,subjectshavingtherapidacetylatorphenotypearerecommended.Inthecaseofrosuvastatin,subjectswiththeorganicanion–transportingpolypeptide1B1c.521T/Tgenotypearerecommended,togetherwithmonitoringofrosuvastatin’scholesterol-loweringeffectatbaselineandDDIphase.Aproof-of-conceptclinicalstudyisbeingplannedbyacollaborativeconsortiumtoevaluatetheproposedBCRPDDIstudydesign.IntroductionBreastcancerresistanceprotein(BCRP;ABCG2)isanATP-bindingcassetteeffluxtransportercomprisingahomodimeroftwohalfsubunits(Giacominietal.,2010).BCRPisexpressedinthesmallintestine,liver,blood-brainbarrier,testis,placenta,andmammaryglands(Endresetal.,2006)andlimitssystemicandorganexposureofrelevantsubstrates.BCRPtransportsendogenousandexogenoussubstrateswithdiversephysicochemicalproperties,whichgenerallyincludeapositiveand/ornegativechargebutotherwisespanalargerangeofmolecularweight,lipophilicity,andpermeability(MaoandUnadkat,2005;Nietal.,2010;Robeyetal.,2011).However,theimpactofBCRPonpharmacokinetics(PK)isthemostpronouncedforcompoundswithlowpassivepermeability(Poirieretal.,2014).1Currentaffiliation:DrugMetabolismandPharmacokinetics,ArdeaBioscienceInc.,SanDiego,California.dx.doi.org/10.1124/dmd.114.062174.sThisarticlehassupplementalmaterialavailableatdmd.aspetjournals.org.ABBREVIATIONS:AUC,areaundertheconcentration-timecurve;BCRP,breastcancerresistanceprotein;DDI,drug-druginteraction;EMA,EuropeanMedicinesAgency;FDA,FoodandDrugAdministration;IR,immediaterelease;MRP,multidrugresistance–associatedprotein;NAT,N-acetyltransferase;OATP,organicanion–transportingpolypeptide;PD,pharmacodynamics;P-gp,P-glycoprotein;PK,pharmacokinetics;PPI,protonpumpinhibitor;SNP,singlenucleotidepolymorphism;TKI,tyrosinekinaseinhibitor.490Fromadrugdispositionperspective,BCRPfunctionsprimarilyasanapicaleffluxpumpinenterocytes,attenuatingintestinalabsorptionoflow-permeabilitysubstratedrugs,andasacanaliculareffluxpump,transportingsubstratesfromhepatocytesintobile.UnlikeintestinalBCRP,whichisrate-determiningintheabsorptionoflow-permeabilitysubstratedrugs,intheliver,uptakeisgenerallyrate-determininginhepaticclearanceofdrugsthatpredominantlyrelyoncarrier-facilitatedtransportintotheliverpriortoexcretionintobileviaBCRP.However,whenabasolateraleffluxmechanismisoperational[e.g.,multidrugresista