药物代谢稳定性筛选的研究进展

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*100850R967R969.1A1001-0971200603-0211-042005-10-13Tel010-68180392E-mailwengjunpharm@hotmail.com*Tel010-66932201E-mailluqj66@yahoo.com.cn18%1S99000gⅡMDRMRPOATMcGinnity11Sohlenius-Sternbeck2Ⅱ3Lau4Caco-2HepG2BC2Hep3BP450CYPCYPUGTV79CYP1A2CYP2A6CYP2E1CYP3A4MLC-51122006633312322.10.5~1h2~4hmultiple-time-point-LC-MSClintcassetteanalysisWyeth-Lisssingle-time-point52.2LC-MS10min6Wu7LC-MSstaggeredparallelseparationLC-MSMSLC-MSMSMUXMSMSMSFang8Gilson215968UVTOF-MS3200100µgL-1MS2.3MS/MSMSNMRNMRLC-NMRLC-NMR-MS2.4CYPⅡNADPHNADPH-P450b5NADPH1NADPHNADPHCYPNADPHCYPNADPH2CYP3CYP4reactiveoxygenspeciesROSCYPROS1CYPROS2ROSROS212ForeignMedicalSciencesSectionofPharmacy2006Jun333NADPH3Houston9VmaxKmClintscalingfactorClintClintvenousequilibriumwellstirredpa-ralleltubeClintClHClint10ClintGiuliano11linearextrapolationinthesta-bilityassayLESAClintClintMcGinnity150ClintClint73%2Yamamoto12CYP2D6relativeactivityfactorRAF4Lam13ClintS9AstraZeneca48S9144ADME1-2QSARCYPTanaka15CYP2C5CYP3A4Ph4Dock14KmCYP3A4Williams16CYP2C9CYP3A4CYPdeGroot17CYP2C9CYP2C9SARQSAR-QSPRCrivori18VolSurf/GRIDALMONDcDNACYP3A475%3122006633385%Shen19QSPRS91074025%33-KsKmKi5ADME1McGinnityDFSoarsMGUrbanowiczRAetal.EvaluationoffreshandcryopreservedhepatocytesasinvitrodrugmetabolismtoolsforthepredictionofmetabolicclearanceJ.DrugMetabDispos200432111247-1253.2Sohlenius-SternbeckAKSchmidtS.Impairedglutathione-conjugat-ingcapacitybycryopreservedhumanandrathepatocytesJ.Xeno-biotica2005357727-736.3GebhardtRHengstlerJGMullerDetal.Newhepatocyteinvitrosystemsfordrugmetabolismmetaboliccapacityandrecommendationsforapplicationinbasicresearchanddrugdevelopmentstandardop-erationproceduresJ.DrugMetabRev2003352/3145-213.4LauYYChenYHLiuTTetal.EvaluationofanovelinvitroCaco-2hepatocytehybridsystemforpredictinginvivooralbioavail-abilityJ.DrugMetabDispos2004329937-942.5DiLKernsEHGaoNetal.Experimentaldesignonsingle-time-pointhigh-throughputmicrosomalstabilityassayJ.JPharmSci20049361537-1544.6VeutheyJLSouverainSRudazS.Column-switchingproceduresforthefastanalysisofdrugsinbiologicsamplesJ.TherDrugMonit2004262161-166.7WuJT.Thedevelopmentofastaggeredparallelseparationliquidchro-matography/tandemmassspectrometrysystemwithon-lineextractionforhighthroughoutscreeningofdrugcandidatesinbiologicalfluidsJ.RapidCommunMassSpectrom200115273-81.8FangLCournoyerJDemeeMetal.High-throughputliquidchro-matographyultraviolet/massspectrometricanalysisofcombinatorialli-brariesusinganeight-channelmultiplexedelectrospraytime-of-flightmassspectrometerJ.RapidCommunMassSpectrom200216151440-1447.9HoustonJB.UtilityofinvitrodrugmetabolismdatainpredictinginvivometabolicclearanceJ.BiochemPharmacol19944791469-1479.10JonesHMHoustonJB.Substratedepletionapproachfordetermininginvitrometabolicclearancetimedependenciesinhepatocyteandmi-crosomalincubationsJ.DrugMetabDispos2004329973-982.11GiulianoCJairajMZafiuCMetal.Directdeterminationofun-boundintrinsicdrugclearanceinthemicrosomalstabilityassayJ.DrugMetabDispos20053391319-1324.12YamamotoTItogaHKohnoYetal.Predictionoforalclear-ancefrominvitrometabolicdatausingrecombinantCYPscompari-sonamongwell-stirredparallel-tubedistributedanddispersionmod-elsJ.Xenobiotica2005356627-646.13LamJLBenetLZ.Hepaticmicrosomestudiesareinsufficienttocharacterizeinvivohepaticmetabolicclearanceandmetabolicdrug-druginteractionsstudiesofdigoxinmetabolisminprimaryrathepato-cytesversusmicrosomesJ.DrugMetabDispos200432111311-1316.14BlanchardNAlexandreEAbadieCetal.Comparisonofclear-ancepredictionsusingprimaryculturesandsuspensionsofhumanhep-atocytesJ.Xenobiotica20053511-15.15TanakaTOkudaTYamamotoY.CharacterizationoftheCYP3A4activesitebyhomologymodelingJ.ChemPharmBullTokyo2004527830-835.16WilliamsPACosmeJVinkovicDMetal.CrystalstructuresofhumancytochromeP4503A4boundtometyraponeandprogesteroneJ.Science20043055684683-686.17deGrootMJEkinsS.PharmacophoremodelingofcytochromesP450J.AdvDrugDelivRev2002543367-383.18CrivoriPZamoraISpeedBetal.ModelbasedonGRID-deriveddescriptorsforestimatingCYP3A4enzymestabilityofpotentialdrugcandidatesJ.JComputAidedMolDes2004183155-166.19ShenMXiaoYGolbraikhAetal.Developmentandvalidationofk-nearest-neighborQSPRmodelsofmetabolicstabilityofdrugcandi-datesJ.JMedChem200346143013-3020.412ForeignMedicalSciencesSectionofPharmacy2006Jun333

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