Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood–brain barriers studied with (R)-[11C]verapamil positron emission tomography 英文参考文献.docVIP

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Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood–brain barriers studied with (R)-[11C]verapamil positron emission tomography 英文参考文献.doc

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Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood–brain barriers studied with (R)-[11C]verapamil positron emission tomography 英文参考文献

Müllaueretal.EJNMMIResearch2012,2:58 /content/2/1/58 ORIGINAL RESEARCH OpenAccess PharmacokineticmodelingofP-glycoprotein functionattheratandhumanblood–brain 11 barriersstudiedwith(R)-[ C]verapamilpositron emissiontomography JuliaMüllauer1,ClaudiaKuntner1,MartinBauer2,JensPBankstahl3,MarkusMüller2,RobAVoskuyl4,5, OliverLanger1,2andStinaSyv?nen5,6* Abstract Background:ThisstudyinvestigatedtheinfluenceofP-glycoprotein(P-gp)inhibitortariquidaronthe pharmacokineticsofP-gpsubstrateradiotracer(R)-[11C]verapamilinplasmaandbrainofratsandhumansbymeans ofpositronemissiontomography(PET). Methods:Dataobtainedfromapreclinicalandclinicalstudy,inwhichpaired(R)-[11C]verapamilPETscanswere performedbefore,during,andaftertariquidaradministration,wereanalyzedusingnonlinearmixedeffects(NLME) modeling.Administrationoftariquidarwasincludedasacovariateontheinfluxandeffluxparameters(Qinand Qout)inordertoinvestigateiftariquidarincreasedinfluxordecreasedoutfluxofradiotraceracrosstheblood–brain barrier(BBB).Additionally,theinfluenceofpilocarpine-inducedstatusepilepticus(SE)wastestedonallmodel parameters,andthebrain-to-plasmapartitioncoefficient(VT-NLME)wascalculated. Results:Ourmodelindicatedthattariquidarenhancesbrainuptakeof(R)-[11C]verapamilbydecreasingQout .The reductioninQout inratsduringandimmediatelyaftertariquidaradministration(sevenfold)wasmorepronounced thaninthesecondPETscanacquired2haftertariquidaradministration(fivefold).TheeffectoftariquidaronQout humanswasapparentduringandimmediatelyaftertariquidaradministration(twofoldreductioninQout)butwas negligibleinthesecondPETscan.SEwasfoundtoinfluencethepharmacologicalvolumeofdistributionofthe in centralbraincompartmentVbr1.TariquidartreatmentleadtoanincreaseinVT-NLME,andpilocarpine-inducedSElead toincreased(R)-[11C]verapamildistributiontotheperipheralbraincompartment. Conclusions:UsingNLMEmodeling,wewereabletoprovidemechanisticinsightintotheeffectsoftariquidarand SEon(R)-[11C]verapamiltransportacrosstheBBBincontroland48hpostSEratsa