化學(xué)結(jié)構(gòu)和藥物代謝

化學(xué)結(jié)構(gòu)和藥物代謝第1頁/共184頁

Section1IntroductionThephysicochemicalpropertiesofdrugsthatpredispose(使偏向于)themtogoodabsorption,suchaslipophilicity(親脂性),areimpediment(妨礙)totheirelimination.Asaconsequence,theeliminationofdrugsnormallyrequirestheirconversionintowatersolublecompoundsbyaprocessofmetabolism,whichenablesexcretionviaurineorfaeces(排泄物).第2頁/共184頁

MetabolismMetabolismisoftenthemajorfactordefiningthepharmacokineticsofdrugs,whichinturncaninfluencetheefficacyandside-effectprofileofthesecompounds.Thechemicalnatureandmeansofidentificationofthesebiotransformationshavebeenwellknownformanyyears,butinrecentyearsmajoradvanceshavebeenmadeintheunderstandingoftheenzymesresponsibleforthemetabolicpathways.第3頁/共184頁Section2EnzymesforDrugMetabolism

（第二節(jié)藥物代謝的酶）

Thedrugmetabolizingenzymesareusuallyclassifiedbythereactionstheycatalyse,aseitherPhaseIorPhaseII.

第4頁/共184頁PhaseIBiotransformationPhaseIreactionsintroduce,orotherwiseproduce,afunctionalgroup(e.g.–OH,-SH,-NH2,-COOH)intothemolecule.Thesereactionincludehydrolysis(水解),reduction(還原)andoxidation(氧化)andareperformedbyawiderangeofenzymes.OftenthesePhaseIreactionsprecedePhaseIIbiotransformations.第I相生物轉(zhuǎn)化主要是官能團(tuán)反應(yīng)，包括對藥物分子的氧化、還原和羥化等，在藥物分子中引入或暴露極性基團(tuán)，如羥基、羧基、巰基和氨基。第5頁/共184頁PhaseIIBiotransformationPhaseIIreactionsinvolvetheconjugation(軛合)onasuitablechemicalgroupofthemolecule(parentcompoundormetabolite)andmanydrugscontainsuitablefunctionalgroupswithoutrecourse(依賴)toPhaseImetabolism.PhaseIIreactionsincludeconjugationwithglucuronic(葡萄糖醛酸)acid,sulfate,glutathione(谷光苷肽)oraminoacids(e.g.glycine(甘氨酸),taurine(牛磺酸),glutamine(谷氨酰胺),allofwhichincreasethewatersolubilityofthemolecule.Conjugationreactions,suchasN-acetylationofaminesandN-,O-andS-methylation,generallyresultinmorelipophilicproducts.第6頁/共184頁1.CytochromeP-450enzymesystem（CYP-450）(細(xì)胞色素P-450酶系)CytochromeP-450enzymesystem(CYP-450)areagroupofnonspecificenzymes(Heme-coupledmonooxygenases)inlivermicrosomes.Inaanotherword,CYP450isaliverhomogenate(勻漿)fractionderivedfromsmoothendoplasmicreticulum(光滑內(nèi)質(zhì)網(wǎng)).CYP-450是一組鐵原卟啉偶聯(lián)單加氧酶，位于肝微粒體中，是主要的藥物代謝酶系。CYP-450屬于體內(nèi)的氧化－還原酶，主要進(jìn)行氧化反應(yīng)，需要NADPH和氧分子共同參與。也能進(jìn)行還原反應(yīng),將含偶氮和硝基還原成芳香伯胺。

第7頁/共184頁2.Reductionenzymesystem(還原酶系)CYP-450酶系（CYP-450）醛－酮還原酶(ketoreductase)：屬于氧化－還原酶。需要NADPH或NADP作為輔酶。谷胱甘肽氧化還原酶(glutathioneoxido-reductase)醌還原酶第8頁/共184頁3.OtheroxidativeenzymesFlavinmonooxygenase(黃素單加氧酶)Monoamineoxidase(單胺氧化酶)Aldehydeoxidase(醛氧化酶)第9頁/共184頁FlavinMonooxygenase(FMO)

(黃素單加氧酶)TheFMOaremicrosomalenzymesandmanyofthereactionstheycatalysecanalsobecatalysedbycytochromeP450.ThecommonestFMOreactionistheoxidationofnucleophilictertiaryaminestoN-oxides,althoughprimaryandsecondaryaminesandseveralsulfur-containingdrugsarealsosubstrates.FMO通常對N和S雜原子進(jìn)行氧化，而不發(fā)生雜原子的脫烷基化反應(yīng)。第10頁/共184頁Monoamineoxidase(MAO)(單胺氧化酶)MAOisinvolvedintheoxidativedeaminationofamines.Substratesincludeanumberofendogenous(內(nèi)源的)amines.第11頁/共184頁AldehydeoxidaseAldehydeoxidasecanoxidizeanumberofsubstitutedpyrroles(吡咯),pyridines(吡啶),primidinesandpurines(嘌呤).Anditssubstratesincludemethotrexate(甲氨蝶呤),quinidine(奎尼定)andcyclophosphamide(環(huán)磷酰胺).第12頁/共184頁HydrolysisEsterase(酯酶)Ingeneral,estersandamidesarehydrolyzedbyenzymesintheblood,livermicrosomes,kidneys,andothertissues.Estersarerapidlyhydrolyzedbyesterases.水解酶位于血漿、肝、腎和腸中，參與酯和酰胺的水解。但酰胺較穩(wěn)定而難水解。第13頁/共184頁EsterasesAcetylcholinesterase(乙酰膽堿酯酶)cholinesterase(pseudocholinesterase擬膽堿酯酶)Arylesterase(芳基酯酶)Livermicrosomalesterases(肝微粒體酯酶)Otherunclassifiedliveresterases環(huán)氧化物酶等。第14頁/共184頁Table1ThedrugmetabolizingEnzymesEnzymePhaseReactionLocalicationAlcohol(醇)dehydrogenaseIOxidationCytosol(胞質(zhì)溶膠)Aldehyde(醛)dehydrogenaseIOxidationMitochondria,CytosolAldehydeoxidaseIOxidationCytosolCarbonyl(羰基)reductaseIReductionandOxidationCytosolCarboxylesterase(酯酶)IHydrolysisMicrosomes,CytosolCytochromeP450IOxidationorReductionMicrosomesDiamineoxidase(氧化酶)IOxidationMitochondria（線粒體）Epoxide(環(huán)氧化物)hydrolaseIHydrolysisMicrosomes,CytosolFlavin(黃素)MonooxygenaseIOxidationMicrosomes第15頁/共184頁Table1ThedrugmetabolizingEnzymesGlucuronyltransferaseIIConjugationMicrosomesGlutathioneS-transferaseIIorIConjugationorreductionCytosol,MicrosomesMonoamine(單胺)oxidaseIOxidationMitochondriaN-acetyltransferaseIIConjugationMitochondria,CytosolPeptidase(肽酶)IHydrolysisBlood,lysosomes(溶酶體）Quinone(醌)oxidoreductaseIReductionCytosolSulfotransferase(硫轉(zhuǎn)移酶)IIConjugationCytosolXanthine(黃嘌呤)oxidaseIOxidationCytosol第16頁/共184頁Section3PhaseIBiotransformation1.Oxidations2.Reductions3.Dehalogenation4.Hydrolysis第17頁/共184頁1.OxidationsI.OxidationofcompoundscontainingCII.OxidationofcompoundscontainingNIII.O-dealkylationofethers

IV.OxidationofcompoundscontainingSV.Oxidationofalcoholandaldehydes第18頁/共184頁I.OxidationofcompoundscontainingCA.AromatichydroxylationB.OlefinicoxidationC.Aliphaticandalicyclichydroxylations第19頁/共184頁A.Aromatic(芳香族的)Hydroxylation

CYP-450toxicitymain第20頁/共184頁Characteristicsofaromatichydroxylation(1)

1.Formonosubstitutedbenzenecompounds,parahydroxylationusuallypredominates,withsomeorthoproductbeingformed.2.Incaseswherethereismorethanonephenylring,onlyoneringisusuallyhydroxylated.第21頁/共184頁Phenytoin

(苯妥英)第22頁/共184頁Phenylbutazone

(保泰松)HighpotencyLesstoxicity第23頁/共184頁Characteristicsofaromatichydroxylation(2)3.Thepositionofhydroxylationcanoftenbeinfluencedbythetypeofsubstituentsontheringaccordingtothetheoriesofaromaticelectrophilicsubstitution.Electrondonatingsubstituentsenhance,whereaselectronwith-drawingsubstituentsreduceorpreventhydroxylation.4.Stericfactorsmustalsobeconsidered,becauseoxidationusuallyoccursattheleasthinderedposition.第24頁/共184頁Clonidine

(可樂定)第25頁/共184頁Probenecid

(丙磺舒)第26頁/共184頁Chlorpromazine

（氯丙嗪)第27頁/共184頁Naphthalene

（萘環(huán))Naphthaleneandhalobenzenesafford1,2-dihydrodiolsandglutathioneconjugatesbecauseofastableepoxide.第28頁/共184頁Polycyclicaromatichydrocarbons

(carcinogenesis)第29頁/共184頁AttentionHowever,itshouldbepointedoutthatwhereothercompetitivepathwaysofbiotransformationexist,theimportanceofareneoxideformationcanbediminished.Morevulnerablesubstituentswillbemetabolizedpreferentially,thusfacilitatingexcretion.第30頁/共184頁B.Olefinic(烯烴)Oxidation

Olefinicoxidationisanalogoustoaromaticoxidation,involvinganepoxideintermediate.Stableepoxidesandvicinaldihydrodiolshavebeenisolated.

第31頁/共184頁Carbamazepine

（卡馬西平）第32頁/共184頁AflatoxinB1

（黃曲霉素）第33頁/共184頁C.Aliphafic(脂肪族)andAlicyclic(脂環(huán)族)Hydroxylations

priority第34頁/共184頁AliphaficandAlicyclicHydroxylationsAlkylsidechainsCarbonsadjacenttoSP2carbon

Alicyclic

(脂環(huán)族)第35頁/共184頁SodiumValproate

（丙戊酸鈉）Alkylsidechains第36頁/共184頁Amobarbitar

（異戊巴比妥）第37頁/共184頁Ibuprofen

（布洛芬）

第38頁/共184頁OxidationofCadjacenttoSP2carbonThemethylenegroupsadjacenttoSP2carbongenerallyareactivatedposition,e.g.,αtoacarbonyl;αtoadoublebond(allyl,烯丙基);αtoaphenylring(benzyl).TheyareoxidizedtothehydroxymethylderivativebyCYP－450.第39頁/共184頁Diazepam（地西泮）Temazepam替馬西泮αtoacarbonyl第40頁/共184頁Tolbutamide

（甲苯磺丁脲）benzyl第41頁/共184頁Toluenebenzyl第42頁/共184頁Pentazocin（鎮(zhèn)痛新）allyl第43頁/共184頁Tetralin(1,2,3,4-tetranaphthalene)Alicyclicbenzyl第44頁/共184頁Acetohexamide

（醋磺己脲）Alicyclic第45頁/共184頁II.OxidationofcompoundscontainingN

A.N-DealkylationB.N-Oxidation第46頁/共184頁A.N-DealkylationThemechanismfortheN-dealkylationreactionisoxidationoftheα-carbon,generatinganunstablecarbinolamine（甲醇胺）thatcollapsestoyieldtheN-dealkylatedsubstrateandthecarbonylderivativeofthesubstituent.第47頁/共184頁ClassificationofN-Dealkylation第48頁/共184頁Propranol（普萘洛爾）第49頁/共184頁Amphetamine（苯丙胺）第50頁/共184頁CharacteristicsofN-Dealkylation1.SomeoftheNsubstituentsremovedbyoxidativedealkylationaremethyl,ethyl,n-propyl,isopropyl,n-butyl,allyl,benzyl,andothershavinganα-H.2.Substituentsthataremoreresistanttodealkylationincludethetert-butyl(noα-H)andthecyclopropylmethyl.3.Ingeneral,tertiaryaminesaredealkylatedtosecondaryaminesfasterthansecondaryaminesaredealkylatedtoprimaryamines.第51頁/共184頁Katamine（氯胺酮）第52頁/共184頁Lidocaine（利多卡因）toxicity第53頁/共184頁Imipramine（丙咪嗪）Desipramine地昔帕明Imipramine第54頁/共184頁N-Isopropylmethoxamine第55頁/共184頁B.N-OxidationTertiaryaminesareoxidizedtotheN-oxides;whereassecondaryandsomeprimaryaminesareconvertedintohydroxylamines(羥胺).Theformationofhydroxylaminesmayaccountforthetoxicityofmanyaromaticamines.第56頁/共184頁FMO、CYP－450andMAON-Oxidation

noα-hydrogenReversible可逆Tertiaryamines第57頁/共184頁Guanethidine（呱乙啶）stableTertiaryamines第58頁/共184頁Dapsone（氨苯砜）抗麻風(fēng)藥noα-hydrogen第59頁/共184頁Themechanismwhichsomearomaticprimeandsecondaryaminesoxidetoeffecttoxicity第60頁/共184頁

Acetaminofluorene

(2－乙酰氨基芴)第61頁/共184頁

III.O-DealkylationofethersOxidativeO-dealkylationofethersisacommonmetabolicreaction.Themajorityofethergroupsindrugmoleculesarearomaticethers.Theseethersareoxidizedbylivermicrosomaloxidases.第62頁/共184頁ThemechanismofO-dealkylationThemechanismofdealkylationisanalogoustothatofN-dealkylation,oxidationoftheα-carbon,andsubsequentdecompositionoftherelativelyunstablegemdiol.Thesubstituentalkylgroupleavesasacarbonylderivative.gemdiol第63頁/共184頁Codeine（可待因）第64頁/共184頁Phenacetin(非那西汀)第65頁/共184頁Indomethacin

（吲哚美辛）第66頁/共184頁InfluencingfactorstotherateofO-dealkylation1.TherateofO-dealkylationisafunctionofchainlength,i.e.,increasingchainlengthreducestherateofdealkylation.2.Stericfactorsandringsubstituentsinfluencetherateofdealkylation,butarecomplicatedbyelectroniceffects.3.Somedrugmoleculescontainmorethanoneethergroup,inwhichcase,usuallyonlyoneetherisdealkylated.第67頁/共184頁Methoxamine（甲氧明）第68頁/共184頁IV.OxidationofcompoundscontainingsulfurA.S-DealkylationB.OxidativeS-DesulfurationC.S-Oxidation第69頁/共184頁6-Methylmercaptopurine

(6-甲硫嘌呤)A.S-DealkylationactiveanticancerdrugCYP－450第70頁/共184頁B.OxidativeS-DesulfurationC=OP=OP=SC=S第71頁/共184頁Thiopental(硫噴妥)S-DesulfurationMono-oxygenase第72頁/共184頁殺蟲藥對硫磷S-DesulfurationMonooxygenase第73頁/共184頁C.S-Oxidation第74頁/共184頁Thioridazine(硫利達(dá)嗪)S-OxidationHigheractivity第75頁/共184頁免疫抑制劑

Oxisuran第76頁/共184頁V.OxidationofAlcohols

AlcoholdehydrogenaseisanNAD-specificenzymelocatedinthesolublefractionoftissuehomogenates(組織勻漿).Itexhibitsabroadspecificityforalcohols.第77頁/共184頁MetabolismsofAlcoholsMostprimaryalcoholsaldehydesothersecondarytertiaryalcoholsSomesecondaryalcoholsconjugationketonesexcretionacid第78頁/共184頁Oxidationofethanolethanoldehydrogenaseamicrosomalenzymesystem(M.E.O.S.)2/3InintoxicationEthylaldehyde1/3第79頁/共184頁OxidationofMethanol

Methanol

dehydrogenaseformaldehyde1/6therateofethanolcatalase（過氧化氫酶）

xanthine(黃嘌呤）oxidaseEthanoldepressestherateofmethanoloxidationbyactingasacompetitivesubstrateforalcoholdehydrogenase,reducingtheformationofthetoxicmetabolite.

第80頁/共184頁Mefenamic（甲滅酸）第81頁/共184頁XanthineoxidasealdehydeoxidasedehydrogenaseOxidationofAldehydesEndogenousaldehydesPrimaryalcoholsbiogenicaminesexogenousaldehydescarboxylicacids第82頁/共184頁2.ReductionsI.CarbonylreductionII.NO2reductionIII.Azoreduction第83頁/共184頁I.ReductionofketoneKetonesarestabletofurtheroxidationandconsequentlyyieldreductionproductsasmajormetabolites.alcoholsketonesdehydrogenase第84頁/共184頁Acetohexamide(醋磺己脲)S-(-)A.Stereospecific第85頁/共184頁S-(+)-Methadone（美沙酮）S-(-)Stereospecific第86頁/共184頁Naltrexone（納曲酮）

Stereospecific第87頁/共184頁Warfarin（華法林）R-WarfarinquickB.Stereo-selective第88頁/共184頁II.NitroReductionNitrocompoundsarereducedtoaromaticprimaryaminesbyanitro-reductase,presumablythroughnitrosoamineandhydroxylamineintermediates.Thesereductasesarenotsolelyresponsibleforthereductionofazoandnitrocompounds,probablybecauseofreductionbythebacterialflora(細(xì)菌群落）intheanaerobic（厭氧）environmentoftheintestine.

第89頁/共184頁Themechanismofnitroreduction第90頁/共184頁4-Nitroquinoline-1-oxide

(4-硝基喹啉-1-氧化物)第91頁/共184頁Nitrobenzene

（硝基苯）第92頁/共184頁Clonazapam（氯硝西泮）第93頁/共184頁III.AzoReductionAnumberofazocompoundsareconvertedtoaromaticprimaryaminesbyCYP-450,NADPH-CYP-450enzymesysteminthelivermicrosomesandbacterialreductaseintheintestine.第94頁/共184頁Themechanismofazoreduction第95頁/共184頁Sulfasalazine

(柳氮磺胺吡啶）第96頁/共184頁3.DehalogenationOxidativedehydrohalogenation(脫鹵化氫作用)Reductivedehalogenation(還原脫鹵)Hydrolyticdehalogenation(水解脫鹵)第97頁/共184頁OxidativedehydrohalogenationRCH2XRCHOR1R2CHXR1CORRCHX2RCOXCHX3XCOX

RCOCHX2RCOCOXα－HandXCYP-450第98頁/共184頁Chloramphenicol（氯霉素）Oxidativedehydrohalogenation第99頁/共184頁Carbontetrachloride

CCl4induceslivernecrosis(壞死),whichismediatedthroughanactivemetabolite.

第100頁/共184頁ReductivedehalogenationHalothane氟烷（1）第101頁/共184頁OxidativedehydrohalogenationHalothane氟烷（2）第102頁/共184頁4.HydrolysisIngeneral,estersandamidesarehydrolyzedbyenzymesintheblood,livermicrosomes,kidneys,andothertissues.Estersarerapidlyhydrolyzedbyesterases(酯酶).第103頁/共184頁Thereactionofhydrolysis

ROCOR1ROH+R1COOH

RONO2ROH+HNO3

ROSO3HROH+H2SO4

RNHCOR1RNH2+R1COOH第104頁/共184頁Succinylcholine

（氯化琥珀膽堿）第105頁/共184頁Aspirin（阿司匹林）第106頁/共184頁Diphenoxylate

（地芬諾酯）止瀉作用比原藥強5倍diphenoxylicacid地芬諾酸第107頁/共184頁Atropine（阿托品）Estersthatarestericallyhinderedaremoreslowlyhydrolyzedandmayappearunchangedintheurine.50%unchanged

50%unhydrolyzedbiotransformedproducts第108頁/共184頁AmidesaremorestabletohydrolysisthanestersProcainamide（普魯卡因胺）Procaine（普魯卡因）第109頁/共184頁Phthalylsulfathiazole

succinylsulfathiazole第110頁/共184頁PhaseImayproduceoneormoreofthefollowingchangesDecreasedpharmacologicactivity--deactivationIncreasedpharmacologicactivity--activationIncreasedtoxicity--intoxicationAlteredpharmacologicactivity第111頁/共184頁Section4PhaseIIBiotransformationTheconjugatesaremorepolarandlesslipid-solublethantheoriginaldrugand,therefore,willresultinmorerapideliminationofthedrugfromtissues.Theconjugationmechanismsarelargelyresponsibleforthedeactivationandenhancedexcretionofmanydrugs,whichwouldotherwiseremaininthebodyandexertprolongedpharmacologicactivity.

第112頁/共184頁ClassificationofPhaseII1.Glucuronicacidconjugation2.Sulfateconjugation3.Conjugationwithaminoacids4.Glutathioneconjugation5.Acetylation6.Methylation第113頁/共184頁P-aminosalicylicAcetylationO-SulfateconjugationN-GlucuronicacidconjugationO-GlucuronicacidconjugationGlucuronicacidconjugationConjugationwithglycine第114頁/共184頁ActivatedintermediatesinPhaseIIreactionAsarule,theconjugatingintermediatedoesnotreactdirectlywiththedrug,buteitherinanactivatedformorwithanactivatedformofthedrug.Mostoftentheseactivatedintermediatesarenucleotides(核苷酸),andthereactioniscatalyzedbyspecifictransferases(轉(zhuǎn)移酶).第115頁/共184頁1.GlucuronicAcidConjugationGlucuronide(葡萄糖醛酸)formationisoneofthemostcommonroutesofdrugmetabolismandaccountsforamajorshareofthemetabolites.Itssignificanceliesinthereadilyavailablesupplyofglucuronicacidinliverandinthelargenumberoffunctionalgroupsformingglucuronideconjugates.Invariably,theglucuronideconjugatesarepharmacologicallyinactive.Thereactioninvolvesthecondensationofthedrugoritsbiotransformationproductwiththeactivatedformofglucuronicacid,uridinediphosphateglucuronicacid(尿苷-5-二磷酸-α-D-葡糖醛酸,UDPGA).第116頁/共184頁UridineDiphosphateGlucuronicAcid(UDPGA)第117頁/共184頁GlucuronicAcidConjugationX=-O-、-N-、-S-、-OCO-。HXRglucuronyltransferase(UDP-葡醛酸轉(zhuǎn)移酶)βwatersolubility第118頁/共184頁TheactionofglucuronidationWiththeattachmentofthehydrophiliccarbohydratemoietycontaininganionizablecarboxylgroup,alipid-solubledrugcanbeconvertedintoamorewater-solublesubstancethatispoorlyreabsorbedbytherenaltubulesandmorereadilyexcretedinbileorurine,whereitislikelytoberecognizedbythebiliaryorrenalorganicacidtransportsystems.第119頁/共184頁EnterohepaticrecyclingNotallglucuronidesareexcretedbythekidneys,however;someareexcretedintothebile,andthenintotheintestines.Theenzymeβ-glucuronidase(葡糖醛酸酶),whichispresentintheintestines,maythenhydrolyzetheconjugate,releasingthedrugtobereabsorbedandenterintotheenterohepaticshunt.Thisprocessisknownasenterohepaticrecycling.第120頁/共184頁Acetaminophen

(撲熱息痛)第121頁/共184頁Chloramphenicol（氯霉素）第122頁/共184頁Ibuprofen

（布洛芬）第123頁/共184頁Desipramine

(地昔帕明)脂肪胺中堿性較強的伯胺、仲胺結(jié)合能力強，易進(jìn)行軛合反應(yīng)第124頁/共184頁p－Aminosalicylicacid

對氨基水楊酸芳胺的反應(yīng)性小，進(jìn)行葡萄糖醛酸軛合反應(yīng)也比較少第125頁/共184頁Meprobamate

（甲丙氨酯）第126頁/共184頁磺胺噻唑(Sulfathiazole)第127頁/共184頁硫醇第128頁/共184頁硫代羧酸第129頁/共184頁Phenylbutazone

(保泰松)第130頁/共184頁Sulfinpyrazone

(硫吡宗）第131頁/共184頁Morphine（嗎啡）WeakopioidantagonistStrongopioidagonist第132頁/共184頁2.SulfateConjugationTheformationofsulfateconjugatesisacommonbiochemicalreactionforbothendogenouscompoundsandfordrugsandotherforeigncompounds.第133頁/共184頁SulfatereactionAdrugissulfatedbytransferofanactivesulfatefrom3‘-phosphoadenosine-5’-phosphosulfate(3’-磷酸腺苷-5’-磷酰硫酸，PAPS)tothedrugacceptor,thatinvolvessulfokinases(硫激酶)(orsulfotransferases).第134頁/共184頁3‘-Phosphoadenosine-5’-Phospho-Sulfate(PAPS)第135頁/共184頁SulfateConjugationROHR—O—SO3HR+(toxicity)ArOHAr—O—SO3HRNH2R—NHSO3HArNH2Ar—NHSO3HRR’NOHRR’NOSO3HRR’N+

(toxicity)第136頁/共184頁Salbutamol

（沙丁胺醇）第137頁/共184頁TheCharacteristicsofSulfateConjugationGenerally,sulfationisahighaffinity,lowcapacityprocessincontrasttoglucuronidationwhichislowaffinity,highcapacity.Thetotalpoolofsulfateisusuallylimitedandcanbereadilyexhausted.Withincreasingdosesofadrug,therefore,conjugationwithsulfatebecomesalesspredominantpathway.第138頁/共184頁Acetaminophen

(撲熱息痛)Athigherdosestherelativeamountofglucuronideincreases.第139頁/共184頁Sulfateconjugationofsomehydroxylamine(羥胺)formshepatotoxicity(肝臟毒性)andcarcinogenicity(致癌性)第140頁/共184頁3.ConjugationwithAminoAcidsGlycineisthemostcommonaminoacidthatformsconjugateswitharomatic,aryl-aliphatic(芳烷基),andheterocycliccarboxylicacids.第141頁/共184頁Theactiveformofaceticacid(CoASH)第142頁/共184頁Brompheniramine（溴苯那敏）第143頁/共184頁Benzoicacid（苯甲酸）在氨基酸軛合反應(yīng)中，主要是取代的苯甲酸參加反應(yīng)第144頁/共184頁Salicylicacid（水楊酸）第145頁/共184頁4.GlutathioneConjugationGlutathione(GSH)conjugatestoelectrophilicmoietiesofdrugsortheirmetabolites.glycinecysteineglutamicacid第146頁/共184頁GlutathioneS-transferasesappeartohavetwomainrolesOneistheconjugationofpotentiallyharmfulelectrophileswiththeendogenousnucleophile,GSH,therebyprotectingothernucleophiliccentersinthecell,suchasthosethatoccurinproteinsandnucleicacids.Thesecondisameansofexcretionfortheseelectrophiles,becauseonceconjugatedwithGSH,theyareusuallyexcretedinthebileandintheurine.第147頁/共184頁Nucleophilicsubstitutionreaction（SN2)

R-X-YR-X-SG

X=CH2,O,SY=halides,=sulfonate(磺酸酯)=epoxides,GlutathioneS-transferases在體內(nèi)清除由于代謝產(chǎn)生的有害的親電性物質(zhì)第148頁/共184頁GSH在體內(nèi)清除由于代謝產(chǎn)生的有害的親電性物質(zhì)RXR－SGROHR—O—SO3HRSGRR’NOHRR’NOSO3HRR’NSGRCOClRCO－SGCHCl3ClCOClGSCOSG第149頁/共184頁Thepathwayofmercapturicacidsynthesis

mercapturicacids(硫醇尿酸)

excreted第150頁/共184頁Morphine（嗎啡）GSHS-alkenetransferasecatalyzestheconju-gationofGSHwithα,β-unsaturatedcarbonylcompounds,analogoustonucleophilicattackontheβ-carbonofanactivateddoublebond.Michael加成反應(yīng)第151頁/共184頁5.Acetylation

Conjugationreactions,suchasN-acetylationofaminesgenerallyresultinmorelipophilicproducts.第152頁/共184頁AcetylCoARX=RNH2,ArNH2,aminoacid,RSO2NH2,RNHNH2,RCONHNH2第153頁/共184頁Aminosalicylate

(對氨基水楊酸）對堿性較強的脂肪族伯胺和仲胺，乙酰化反應(yīng)通常較少，即使進(jìn)行結(jié)合率也較低。但對于大多數(shù)芳香伯胺，由于其堿性中等極易進(jìn)行乙?；磻?yīng)。第154頁/共184頁Isoniazid

（異煙肼）第155頁/共184頁Conjugationreaction第156頁/共184頁6.MethylationMethylationisacommonbiochemicalreactionbutappearstobeofgreatersignificanceinthemetabolismofendogenouscompoundsthanfordrugsandotherforeigncompounds.Methylationdiffersfromotherconjugationprocessesinthattheproductsformedmayinsomecaseshaveasgreatorgreaterpharmacologicactivitythantheparentmolecule.第157頁/共184頁Theprocessofmethylation第158頁/共184頁MethylationA.O-methylationB.N-methylationC.S-methylation第159頁/共184頁A.O-methylation

TheprocessofO-methylati