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(cid:2) D ow nloaded from https://onlinelibrary.w iley.com /doi/ by ibrahim DRUG METABOLISM HANDBOOK ragab - C ochrane G erm any , W iley O nline Library on [23/11/2022]. See the Term s and C (cid:2) onditions (https://onlinelibrary.w (cid:2) iley.com /term s-and-conditions) on W iley O nline Library for rules of use; O A articles are governed by the applicable C reative C om m ons License (cid:2) (cid:2) D ow nloaded from https://onlinelibrary.w iley.com DRUG METABOLISM /doi/ by ibrahim HANDBOOK ragab - C ochrane G CONCEPTS AND APPLICATIONS IN ermany , W CANCER RESEARCH iley O VSeocluonmdeE1dition nline Library on [23/11/2022]. See the Term s and C (cid:2) EAdlaiteFd.bNyassar onditions (https://onlinelibrary.w (cid:2) YaleUniversity,USA iley.com /term APsasuolciFa.teHEodlilteonrsberg s-and-conditions) on W TheUniversityofMichiganMedical,USA iley O JHSSoaeohAaualtnmhIncneasSntrietcuKaitneatvinonetfsaitNoMursca,lneUanSraAPhysics,IN nline Library for rules of use; OA SZhuejZiaennggUniversity,CH articles are governed by the applicable C reative C om m ons License (cid:2) (cid:2) D ow nloaded from https://onlinelibrary.w iley.com DRUG METABOLISM /doi/ by ibrahim HANDBOOK ragab - C ochrane G CONCEPTS AND APPLICATIONS IN ermany , W CANCER RESEARCH iley O VSeocluonmdeE2dition nline Library on [23/11/2022]. See the Term s and C (cid:2) EAdlaiteFd.bNyassar onditions (https://onlinelibrary.w (cid:2) YaleUniversity,USA iley.com /term APsasuolciFa.teHEodlilteonrsberg s-and-conditions) on W TheUniversityofMichiganMedical,USA iley O JHSSoaeohAaualtnmhIncneasSntrietcuKaitneatvinonetfsaitNoMursca,lneUanSraAPhysics,IN nline Library for rules of use; OA SZhuejZiaennggUniversity,CH articles are governed by the applicable C reative C om m ons License (cid:2) (cid:2) D ow nloaded from T©EJohdh2iisn0ti2soWe3nciJoHloenhiydsnt&oeWrdSyiitolienoysn&(fi1reSs,to2pn0us0,b9Iln)isch.ed2023 https://onlinelibrary.wiley.com Atortalhlnersrimgwhiitsttsee,rdee,xsiecnrevapentdya.sfNoproemrpmaoirrtttbeoydfatbhnyiyslampwue.baAlnicsd,avetiilcoeenctomrnoanhyiocbw,emtroeecpohrbaotndaiiucncaepl,dep,rhmstooitsroseicodonpinytoianrgree,utrrseieceovmradaltisneyrgsitaoelrmfr,oomr /doi/ by ibrahim tTbwhehiitseihdtrileitagnlwehti.tifisoeafdvAaasillaathFbe.leNaauatsthshaotrtrp,sP:/oa/wfutwlhFwe..Hewdiolietlloyer.nciaoblmemr/gga,otJe/oprAiearnlmninisStschiaoistninsw.ao,rSkohuamsebneeKnaanstsieMrtaendnian,aacncdorSduaZnceengto ragab - Cochrane Germ RegisteredOffice any , W JohnWiley&Sons,Inc.,111RiverStreet,Hoboken,NJ07030,USA iley O FpWcTSoororoainrnlddetsdee,yuenmIcatnttalasctsirh.lovskaaipssont:iufdtaWbo/puolupsiirlsreeahiaygttesrlwsasoanwibiftndfiaswllstbi.thaewoatdeioneliWekstdoysai.rinrcilidneaotyhlmpaoelr.ovfiUfinagrctonieveiastet,reyrecdsuoitSosfrtatneoadsltmeeeocmseftrrataohnsrneikdsriscvbooifotcrohoererskmer,gmacainostastduyeanrmnnterododiterbtesbryaeaindpnaferdvoimnarmmital-aaroakybntslin-eodoonieftnmaJboobeathonhunudestW.reWSdfiooliwerlmemyityeh&aotsu.t nline Library on [23/11/2022]. See the Term writtenpermission.Allothertrademarksarethepropertyoftheirrespectiveowners.JohnWiley& s and C (cid:2) SLIcumnoroiegnmnvdessiiidte,tcawIiotnnnoftoceL.r,flfeieoiosvaqwnibnuegiooiwlopitftimyaanin/sngeDsfdnoorietcsre,scmivaoelaataarleitrumddicaoehewtnv,reiiercotteqhehflueaWfaiotnpiianrnym,rfgaropeamtrrnnomototdytamnhutgeiocotodunotisfihrpecervoaroetfvtinhomiddinnoeesgdrd,sicm,cihniaenantnnehytsgei,ceoehpsnqaaieunncdikgpgiaeonmgsveteiehnnirintnst,shmbaeeonretiodnnoktsdar.telriuvnreicsctgteiruousl,ncatstthiioooenrnrsisen,fadaodnirecderaattiishcohen onditions (https://onlinelibrary.w (cid:2) obaippinnceurfcocstruluhtmpusrieoadsaofgsicftwneeoiy.ogoraNontrwnsrkaodiilctanwhsofstoopmaaarurrtpereatcalpmidletniadatmetreteyniinindottmeagsnwstafstiaoaohyonrrnibnsfdteaih/twnohnicgosreyrsrwpeckiaamooo,nttnrtepedhktdlneei.petnoTyirdatrehmslcweeosaaxaofufktaruettercihrnaotcnidnnsteoehtswio.darefWoetsbprfaoyukhrnferisaltmosaehnerleeedtnghrrsatsceanirphnteipeiazfpouocnarnibrttefisimalsociboesanaihnrltl,lieitwywtoaryntadeaiorbvindrsresacdoisfilnte,aaettswin,uimenoertshiosrtaswottplerlfmirnostwohrehdsaaaaraurnelvrcpesaettspanhiuremstatsciitreeatcestdtut,fheoleterarhitrraheeleisdrotor iley.com/terms-and-conditions) on W ppphFblinieurueaucotrbbbriwevtdlllheiiiieenssdeenhhferomntee,arorrrawlrea,aiyshanrcnnedeonydconenoloatrosttsmuebshestqseinmhhsuogsooewefuarunnpgiosltdterdraeioadkabnbtfillidiw,eetonooanoafrrrsosrwesorweniaattyndhrtrmhoieyeeteutrratoeihrynidtnnahsgamfitaemtopnuwarrrakdamceogteobfwiea.eomsstThsin.itmsoeh.einnoiYsesnrlioowitcasruiiltoassessrledhrekdreroviaavinusimdiclcst.edeahoNssgcil.sdteoehTswinwet,hshoiieuonterhlrckratgldttuwamhhvdnieeiatiichnyzupeagnuhaatbdibansovuelpdniertse,shscnctwteiahorareanatlbtindnlseisoigtmgniertwigeeidat,hsteuoohedctrrraohettdpnooatirtrshoaspsapeidpspneuhrpecocadeiptlaalrmlrb,ieaaedtye. iley Online Library for rules of use; O A LICCSSeooiBbtvvriNeenarrr:9yDI9/m71oe81fas1pgiCg1teno1T:9:n©i8Wmg5rUe1eilss0eGTs1yeRC1n[aEsLteEaTtl]NSotgd3inSbg/yS-ihSnut-rPtatueivrbselt,iocCachtkieo.cnnonmDaia,tIanadpiapliedfor: articles are governed by the applicable Creative C om m ons License (cid:2) (cid:2) D ow nloaded from https://onlinelibrary.w iley.com CONTENTS /doi/ by ibrahim ragab - C VOLUME1 ochrane Germ any , W PREFACE xiii iley O (cid:2) LPA1IS.RT1111HTR....O1234oiIsbF.teoCrrtaiOIcC1a1S1NSa998Nnt.oluT050dKTnPd000RitBeRsisn–reO:r–goiI1sscD1Bv9pDk9e5ieUe8sUr0clcs0,TstoCi:i:1eOvvMC9TseeR7IoSro7OynpSd)fiaNoenrrfmnnMiaDnatgirjoouPnrgaDosMtf,reMuPtgraaebMjsooerelnitPstam,abatohnElwdimsamFeyursPgtuaaenrtseh,dwwMiatyhesch(Canoinsttiic x335v81 nline Library on [23/11/2022]. See the Terms and Conditions (https://onlinelibrary.w (cid:2) 1.5 E19n8z0y–m2a0t0ic5:BFaiesilsdDrivenbyImprovedTechnologies 109 iley.com/term 2. 1F.a6ctors2RA0ef0ff5ee+rcet:innHcgeigsMheTteacbhonlioslmogy 111003 s-and-conditions) on W RobertaS.King iley O 3. 3BR.i1oobterratanRDsSf.eorKufremignregMantiecoetnasbsoinlisDmruingDMreutgabDoelivsemlopmentandDrugTherapy 111767 nline Library for rules of use; O A 3333....2453 CRPOEFuranexentfzidaedcyilrtamcyeitotsnioiionosclnaonelsgsoGyafnarMdonudeCptMyaBtboooicodlhititfirreaoenamrssnfedooPfrEmC4n5ayz0ttyioomcnhesr:RoPmehseapsPoen4I5s,i0bPslheaseII,and 2232303914 articles are governed by the applicable C v reative Com m ons License (cid:2) (cid:2) D ow vi4. AJoCeCORoN.mTCEpaNrnTenShoenn,PsirvaekaPsihctVuarcehaosfpBatii,oatnradnYsafongrmYuaatinoninDrugDiscovery 41 nloaded from https://onlinelibrary.w 4.1 Introduction 41 iley.com 444...342 MARanetatealybotoficlMiaslmeTtaeobcfhoSnlmiosmlaollgMiesoilnecDulreusgMetabolism 644563 /doi/ by ibrahim 4.5 DBieogtrraadnesfrosrmationforNovelModalities – PeptidesandProtein 79 ragab - C 4.6 RCoefnecrleunsicoens 9933 ochrane Germ any , W 5. InVivoDrugMetaboliteKinetics 103 iley O 555555Z......234156hengYMPIEDIISannnuhnfeetcfgmaVrteotoeraicmrmvrdbtpmouaoaoorcilcDrfniytaotIiaertokniutnoihingoniebnMtoiitofceifo/tPPanFhhboaaaorrnrmlmimdtaeaIatcnicKoodoilnudnocyeagtntniicioadcamnlCElyioolcinAnmMcMcieontpeidavttteesailobaiMnnongledCittaPelebrKaionrilancitnieepct(leisec)ssoifn 111111320230025753 nline Library on [23/11/2022]. See the Terms and C (cid:2) 6. DLCru-Mg-MS/ARMeetbaSfbeb-rBroeelavniszicaeientdisgoPnErsontzeyommeiscasnMdeTthraondsspfoorrteQrsuantifying 111334753 onditions (https://onlinelibrary.w (cid:2) LoganS.Smith,SunMinJung,JiapengLi,andHao-JieZhu iley.com 6.1 Introduction 143 /term 66..23 MAMMneaaatsshsslyoSSsdppisseeccttrroommeettrryyVDeartsauAsAcqluteisrintiaotniveMPertohtoedinsfQoruaPnrotitfiecoamtioicns 114445 s-and-conditions) on W 6.4 TargetedApproaches 146 iley O 66666.....57896 PULLDRraaenMobbltateeaEetllrioT--gvBFmeerPateiQersceoedsudtPPearPinronorttiotQefietoceoumaomatmniiicoctisniscfisAVcaeptripsorunosaUAchsbienssoglLutCe-QMuSa/MntiSfi-cBaatsioend 111114555572580 nline Library for rules of use; OA 666...111012 LRPCCoCooetfnn-eeMscnriledtuSinesa/MicrloaeAntSsipoMpnlseictohafotiDdosMnoEfTDPMroEtTeinEQxpuraensstiiofincaStitoundiUestilizing 111166660443 articles are governed by the applicable C reative C om m ons License (cid:2) (cid:2) D ow PARTII. TECHNOLOGIESFORINVITROANDINVIVOCSOTNUTEDNITESS 1v7i7i nloaded from https://onlinelibrary.w 7. MThaosmsSaspRec.tSrhoamrpetry 179 iley.com 77..12 IAntBrorideufcHtioisntory 118709 /doi/ by ibrahim 77..34 TMhaessMSapsescStrpoemctertormyeIntrsytrLuimteernattautrieon 118832 ragab - C 77..56 ICnotenrcpluresitoantison:WhatDoesitMean 221514 ochrane Germ References 255 any , W 8. D8888AA....3241crlaicveFel.esNrMMCTIaansotresatiionartttaolrergbiodrcMiofuealcCseifttotEhieaorofbInfLidoecCecelitnt-feMtoifirISdcMeaMnteitetoiatfinhbcoSoadtltiuistodeniCeMshFaaorsasrcwSteaprreidcztartoiomnetryTechnology 222227666609977 iley Online Library on [23/11/2022]. See the Term 88..56 SOtnralitneegiHesDfo-LrCId-MenStifyingUnknownMetabolites 227745 s and C (cid:2) 8888....79180 F“SSMAtuloremlatwlta-meibnfgoao-irOrelyisMcntAeoe”tcSatRcbivraoaedlteiiitonoeanfIcodStrietvuRnidtteyiifiaeDccstaebitvtiyeeocMnMtoaerst,saSSbtpooelpictFetrsloomw,eatrnydDynamic 222288889827 onditions (https://onlinelibrary.w (cid:2) ARebfberreevnicaetisonsandGlossary 229990 iley.com /term 9. MRAolealteFa.boNofalSisctsraSurtcatbuirlaitlyModificationsofDrugCandidatestoEnhance 303 s-and-conditions) on W 9.1 Background 303 iley O 99999.....34562 MSEMAInindgoethrnvtdoaaaiifidbfinncuocctaacaelingttcMiiceooSesnnetootaaffbbEMilointleiyhtcaaaSbnntocdailbniItignelitMtCryihneastaircbaMcotleiecrtiaSzbataotibloiicnlitCaylnedarSatnrucecture 333330000067554 nline Library for rules of use; OA 9999....78910 RSACCtaoenrsfanaeetclreylSeugttniisuceicaodselnisteTossoEonlshanceMetabolicStability 333330221170870 articles are governed by the applicable C reative C om m ons License (cid:2) (cid:2) D ow v1i0ii. CDarnuCdgOiNDdTaeEtseNisgTnStoSItmraptergoivees:PRKoPleaorafmStertuecrtsuoraflNMewodDifircuagtsionsofDrug 323 nloaded from https://onlinelibrary.w AlaF.Nassar iley.com 111000...132 APOKcratiAlvAenabMlsyoestriapsbtioolniteasndIntravenousDose 333323333 /doi/ by ibrahim 1100..45 CPraosderSutgusdtioesIncreaseWaterSolubility 333384 ragab - C 10.6 RCoefnecrleunsicoens 334309 ochrane Germ any , W 11. 1i11111CAn111111hl......Ma624513eFme.diNciDCIPAIKaacdmsieloecensirSpoyayvvaotrlaoselxrTyGllruCieoontdcnalhopcautntrelmuscsacBmeruteeaasiirinnclnoostdtAdDnfriiyRSlnrdetugtearrogatatictaMoTetnnoigvidxniaeeiiRncsmIidnettioyatzSeceaI-rtAmnmtivhdcpeeeyrMdMloT-iCvaooeetlxoteeiaDAsccbuiirtonTlyualhgiDrotiefSMoruaDeCefgsoerctuDetnhyrgcaisesnCcpiosatmvnaedssriAydaaptnpedslied 333333344545555958792 iley Online Library on [23/11/2022]. See the Terms and C (cid:2) 1111111111.....7891101 MPCCCrlaoeeisnncceichlcilSanautnilsuciiDasodtlnieiecDvsaeSenltvoduepdFlmoiueptesumnrtee:nSPttorsastiebgiylities 333336666664043 onditions (https://onlinelibrary.w (cid:2) References 367 iley.com 12. StudiesofReactiveMetabolitesusingGenotoxicityArraysand /term E1J2anm.1zeysmFe.IR/nDutrNsoliAdnguBcatniiodocnEolliloGi.dHsv–as2tk0o2v1s 337733 s-and-conditions) on W 12.2 OnDemandMetabolicReactions 374 iley O 11112222....3456 GAAEEDlCdeererntdLcaeeutycrAscstotircnwiorhgianetyShmsitEicelalu-eSnmcptMiernoceeciasfihcsceeumDnretiacABmaorlartDgaheyeDstteoNcTtAiUoOnMxOidRatSioUnPaPnRdENSuScOleRobase 333387978926 nline Library for rules of use; OA 1122..78 ABRECimoecokfnegencrrrlogaeuwipnsnhiclgoeeiendsTssgemachnendnotFlsougtuieresaOnudtlMooekthods 333339999989994 articles are governed by the applicable C reative C om m ons License (cid:2) (cid:2) D ow PARTIII. DRUGINTERACTIONS CONTENTS 40ix7 nloaded from https://onlinelibrary.w 13. EPanuzlyFm.HeoInllehnibbeitrigon 409 iley.com 1133..21 MInetrcohdauncitsimonsofEnzymeInhibition 441019 /doi/ by ibrahim 1133..34 CNoomncpoemtiptievteitIivnehiIbnihtiiobnition 441132 ragab - C 1133..56 UPrnocdoumctpIentihtiibveitiIonnhibition 441144 ochrane Germ 13.7 Transition-StateAnalogs 415 any , W 1111111133333333........91181111452301 CMPISRQISnnluaoeuoehhrbvvawctiiseabbihs,tarliiiraTe-lttsaInioinIiotrbgnirtersnlshlheemyIttvoin-hbIA-eBfnhBairtCthiitsiatbnoiiyaasbbidnetctrliioiehedtnocogMnItIhronnsIrehaontthicmhabteibiiebvtoEoiaPtlrntoi4ozszr5erys0sdmEteonRzyemacetsiveProductsthat 444444442221111195105918 iley Online Library on [23/11/2022]. See the Term 13.16 Mechanism-BasedInactivators 422 s and C (cid:2) 14. aXHneodnnoDgbbiiisnoRpgtoeiWcsfeiaRtrineoegnncaecnepdstoWre-MnXedieiatedGeneRegulationinDrugMetabolism 442247 onditions (https://onlinelibrary.w (cid:2) 1144..21 PInrtergondauncetiXonReceptor 442297 iley.com 14.3 ConstitutiveAndrostane/ActivatedReceptor(CAR) 441 /term 14.4 ARClecokfsenirnoegwncRleeedsmgmareknstsandPerspectives 444555233 s-and-conditions) on W 15. CharacterizationofCytochromeP450MechanismBasedInhibition 465 iley O 111D555a...123nA.RAIIInnnopthhcrokiiobbpadiirttnuooodctrrteLssiioattnhhrnraayttCUI.nWpteoirenancAktecrintsivaaPtisoenudBoinirdreCvoevrsailbelnetMlyatonntherewPi4t5h0 447655 nline Library for rules of use; OA 15.4 HGCRInoeeraofvmceautreilpeve,InanrOtctoileofynstneMnthoTaditimfCyeastuhLseeeAaDdpeionspgtrrutooctetHiionenmoef-tDheerPivreodstPherotidcuHctesmtheat 445781580 articles are governed by the applicable C reative C om m ons License (cid:2) (cid:2) D ow x16. ACCanOrlINnDTtEarNvoiTdsSuctiontoMetabolicReaction-Phenotyping 527 nloaded from https://onlinelibrary.w 16.1 Introduction 527 iley.com 111666...423 ISCniogVmniimtfircooantnotInIDnVrVuitgirv-ooMMEeetxatthbraoopdlioszlitanotgioAEnsnsozefysMmsDeestraubgoMlicetCalbeoalriasnmce 555323489 /doi/ by ibrahim 16.5 RSuemfemreanrcyes 554466 ragab - C 17. EpigeneticRegulationofDrug-MetabolizingEnzymesinCancer 553 ochrane Germ JiaqiWang,XiaoliZheng,andSuZeng any , W 17.1 Introduction 553 iley O 1111177777.....23456 ARDHNRCleoNcNioskfntAsAenocirnooneMMgdwenicReelMneettgehdhsomygyRdlmlaaiaNfirttekAicinooastnntsaionondfDPeMrsEpsectives 555555565666553844194 nline Library on [23/11/2022]. See the Term 18. EpigeneticRegulationofDrugTransportersinCancer 573 s and C (cid:2) 1111Y8888i....n2341gyingDHNInWoNitsrnatAonocdgonM,udeYcieMntinitgohgonyRZdliaNhfitoAciuoa,sntYiounWsang,LushanYu,andSuZeng 555577879513 onditions (https://onlinelibrary.w (cid:2) 18.5 ClosingRemarksandPerspectives 591 iley.com Acknowledgments 592 /term VOLUME2References 592 s-and-conditions) on W iley O PLPARISERTFTOAIFCV.ECOTNOTXRIICBIUTTYORS 6x0ixi5ii nline Library for rules of use; O A 1209.. ATUMhlmaleerekrRsghPoi.MclGeR.roHeilflaaoDcntuirmoungegsMotwoedtDaabraunogdlissCmarilnDTaovixsicity 667077 articles are governed by the applicable C reative C om m ons License (cid:2)