Alcohol ADME in Primates Studied with Positron Emission Tomography 英文参考文献.docVIP

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Alcohol ADME in Primates Studied with Positron Emission Tomography 英文参考文献.doc

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Alcohol ADME in Primates Studied with Positron Emission Tomography 英文参考文献

AlcoholADMEinPrimatesStudiedwithPositron EmissionTomography ZizhongLi1*,YouwenXu1,DonWarner1,NoraD.Volkow2,3 1MedicalDepartment,BrookhavenNationalLaboratory,Upton,NewYork,UnitedStatesofAmerica, 2NationalInstituteonAlcoholAbuseandAlcoholism,Bethesda, Maryland,UnitedStatesofAmerica,3NationalInstituteonDrugAbuse,Bethesda,Maryland,UnitedStatesofAmerica Abstract BackgroundandPurpose:Thesensitivitytotheintoxicatingeffectsofalcoholaswellasitsadversemedicalconsequences differmarkedlyamongindividuals,whichreflectsinpartdifferencesinalcohol’sabsorption,distribution,metabolism,and elimination (ADME) properties. The ADME of alcohol in the body and its relationship with alcohol’s brain bioavailability, however,isnotwellunderstood. ExperimentalApproach:TheADMEofC-11labeledalcohol,CH311CH2OH,1andC-11anddeuteriumduallabeledalcohol, 11 CH3 CD2OH, 2 in baboons was compared based on the principle that C–D bond is stronger than C–H bond, thus the reactionisslowerifC–Dbondbreakingoccursinarate-determiningmetabolicstep.ThefollowingADMEparametersin peripheralorgansandbrainwerederivedfromtimeactivitycurve(TAC)ofpositronemissiontomography(PET)scans:peak uptake(Cmax);peakuptaketime(Tmax),half-lifeofpeakuptake(T1/2),theareaunderthecurve(AUC60min),andtheresidue uptake(C60min ). KeyResults:For1thehighestuptakeoccurredinthekidneywhereasfor2itoccurredintheliver.Adeuteriumisotope effectwasobservedinthekidneysinbothanimalsstudiedandintheliverofoneanimalbutnottheother.Thehighest uptakefor1and2inthebrainwasinstriatumandcerebellumbut2hadhigheruptakethan1inallbrainregionsmost evidentlyinthalamusandcingulate.Alcohol’sbrainuptakewassignificantlyhigherwhengivenintravenouslythanwhen givenorallyandalsowhentheanimalwaspretreatedwithapharmacologicaldoseofalcohol. ConclusionandImplications:Thestudyshowsthatalcoholmetabolisminperipheralorganshadalargeeffectonalcohol’s brainbioavailability.Thisstudysetsthestageforclinicalinvestigationonhowgenetics,genderandalcoholabuseaffect alcohol’sADMEanditsrelationsh