急性毒性试验的研究进展

ChineseJournalofNewDrugs2009,18(21)202420091821[],,,,:[phone],E2mail:[e-mail],,(,100038)[]ICHM3,,3R,,,[];;(LD50)[]R965.3[]A[]1003-3734(2009)2024-04AdvanceinstudiesofacutedrugtoxicityWANGQing2li,WANGHai2xue,MALei(CenterforDrugEvaluation,StateFoodandDrugAdministration,Beijing100038,China)[Abstract]Traditionally,singledosetoxicitystudiesinanimals,programmedinearlyphaseofnewdrugdevelopment,areusuallyrequiredforanypharmaceuticalsintendedforhumanuse.Internationalconferenceonharmonizationoftechnicalrequirementsforregistrationofpharmaceuticalsforhumanuse(ICH)andtheguidelineM3discussedthescientificbackgroundofthestudy,andrecommendedthedevelopmentstrategiesandrequirementsforregistration.Inrecentyears,withtheshareofnonclinicalsafetystudiesconductedbetweencompaniesandtheconsiderationofthe3Rsprinciples,suggestionsinrefiningthesingledosetoxicitystudywerepresented.[Keywords]acutetoxicity;singledosetoxicity;LD50,(acutetoxicitystudy,singledosetoxicitystudy,SDT),,(ICH)(M3)SDT2005(SFDA),,ICH,,,3R(refinement,reduction,replacement),SDT,ICHM3SDTSDT,SDT1SDT1991ICH,(OECD)SDT,SDT,,(LD50),,,LD50[1]ChineseJournalofNewDrugs2009,18(21)202520091821111LD50LD50,ICH,LD503R[2],LD50,,21448138[3]2002,,,SDT,SDT,,LD50,,:,;;,;,,LD50,LD50,,LD50,,SDTLD50,1LD50LD50/mgkg-1683217302.272649210742.182489425502.852519512786.552570450007.1012000-2002,12SDTGLP,GLP,112SDTSDTSDT,SDT,,,SDT,SDT,,,,SDTSDTICHSDT,18,74,SDT[4],SDT,2428SDT,22(20%),62SDT,SDT,,SDT,24,,,,4019,,SDT;SDT,GLP;;,,SDT;;,2ICHM3SDTM3ChineseJournalofNewDrugs2009,18(21)202620091821,M3(1997)M3(R1)(2000),SDT,SDT,,ICH1M3(R2)[5],,,SDTM3(R2),,(CmaxAUC)50,SDTSDT,,,M3(R2)III,,M3,,,M3(R2),SDT,,M3(R2),(),1g,20001000mgkg-1d-1,,,50,32005SFDA[6],ICHOECD,,,LD50,,,M3(R2),,,,,,,,,,,;,,,SDT,,M3(R2)SDT,,,,,,,M3(R2),,,,SDT,SDT,,,,4,SDT,,SDT,,ICHM3(R2),,,,,SDT(2027)ChineseJournalofNewDrugs2009,18(21)202720091821:,,,,():,,,,,,,,1/3,,(S111),,15mgkg-1;,:,,(PostAbsorption/MetabolismDrug,PAMD)PAMD,,,PAMD,,,,,:,,,SSRI,,,,,,,S111,(),:()(2026)[][1],.[J].,2004,13(11):961-964.[2]CORDIERA.Singledosetoxicity:Industryperspectives//Proceed2ingsoftheFirstInternationalConferenceonHarmonization,1991[C].Brussels:TheQueen’sUniversityofBelfast,1991:189-191.[3]ZBINDENG,FLURY2ROVERSIM.SignificanceoftheLD502testforthetoxicologicalevaluationofchemicalsubstances[J].ArchToxicol,1981,47(2):77-99.[4]ROBINSONS,DELONGEASJL,DONALDE,etal.AEuropeanpharmaceuticalcompanyinitiativechallengingtheregulatoryre2quirementforacutetoxicitystudiesinpharmaceuticaldrugdevel2opment[J].RegulToxicolPharmacol,2008,50(3):345-352.[5]ICH.GuidelineM3(R2):Nonclinicalsafetystudiesforthecon2ductofhumanclinicaltrialsandmarketingauthorizationforphar2maceuticals[EB/OL].(2008-07-01)[6].[EB/OL].(2005-03-09):/:2009-02-23