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1、REVIEWSManagingthechallengeofchemicallyreactivemetabolitesindrugdevelopmentB. KevinPark*,AlanBoobis‡,StephenClarke§,ChrisE.P.Goldring*,DavidJones
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3、,J. GerryKenna¶,CraigLambert#,HughG.Laverty*,DeanJ.Naisbitt*,SidneyNelson**,DeborahA.Nicoll-Griffith‡‡,R.ScottObach§§,PhilipRoutle
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8、,DennisA. Smith¶¶,DonaldJ. Tweedie##,NicoVermeulen***,DominicP.Williams*,IanD.Wilson‡‡‡andThomasA. Baillie§§§Abstract
9、Thenormalmetabolismofdrugscangeneratemetabolitesthathaveintrinsicchemicalreactivitytowardscellularmolecules,andthereforehavethepotentialtoalterbiologica
10、lfunctionandinitiateseriousadversedrugreactions.Here,wepresentanassessmentofthecurrentapproachesusedfortheevaluationofchemicallyreactivemetabolites.Wealsodescribehowtheseapproachesarebeingusedwithinthepharmaceuticalindustrytoassessandminimizethepotentialofdrugcandidatestocause
11、toxicity.Atearlystagesofdrugdiscovery,iterationbetweenmedicinalchemistryanddrugmetabolismcaneliminateperceivedreactivemetabolite-mediatedchemicalliabilitieswithoutcompromisingpharmacologicalactivityortheneedforextensivesafetyevaluationbeyondstandardpractices.Inthefuture,reacti
12、vemetaboliteevaluationmayalsobeusefulduringclinicaldevelopmentforimprovingclinicalriskassessmentandriskmanagement.Currently,thereremainsahugegapinourunderstandingofthebasicmechanismsthatunderliechemicalstress-mediatedadversereactionsinhumans.ThisReviewsummarizesourviewsonthisc
13、omplextopic,andincludesinsightsintopracticesconsideredbythepharmaceuticalindustry.Adversedrugreactions(ADRs)areamajorcomplicationpredictablefromourunderstandingofitsmetabolism;ofdrugtherapyandanimpedimenttodrugdevelop-however,manyotherdrugscauseidiosyncraticdrug-mentandclinica
14、luseaftermarketing.Asaconsequenceinducedliverinjury,which,althoughrareandunpre-ofevidenceoftoxicity,16outof548(2.9%)newchemicaldictable,cancausesignificantmorbidityandmortality.entitiesthatwereapprovedfortheUSmarketbetweenStudieswithmodelcompoundsanddrugs—suchas1975and1999were
15、subsequentlywithdrawnfromtheacetaminophen—havehelpedtodefinet
