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(yè)/共184頁(yè)

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

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

（第二節(jié)藥物代謝的酶）

Thedrugmetabolizingenzymesareusuallyclassifiedbythereactionstheycatalyse,aseitherPhaseIorPhaseII.

第4頁(yè)/共184頁(yè)P(yáng)haseIBiotransformationPhaseIreactionsintroduce,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(duì)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(yè)/共184頁(yè)P(yáng)haseIIBiotransformationPhaseIIreactionsinvolvetheconjugation(軛合)onasuitablechemicalgroupofthemolecule(parentcompoundormetabolite)andmanydrugscontainsuitablefunctionalgroupswithoutrecourse(依賴(lài))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(yè)/共184頁(yè)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(yè)/共184頁(yè)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(yè)/共184頁(yè)3.OtheroxidativeenzymesFlavinmonooxygenase(黃素單加氧酶)Monoamineoxidase(單胺氧化酶)Aldehydeoxidase(醛氧化酶)第9頁(yè)/共184頁(yè)FlavinMonooxygenase(FMO)

(黃素單加氧酶)TheFMOaremicrosomalenzymesandmanyofthereactionstheycatalysecanalsobecatalysedbycytochromeP450.ThecommonestFMOreactionistheoxidationofnucleophilictertiaryaminestoN-oxides,althoughprimaryandsecondaryaminesandseveralsulfur-containingdrugsarealsosubstrates.FMO通常對(duì)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(yè)/共184頁(yè)Monoamineoxidase(MAO)(單胺氧化酶)MAOisinvolvedintheoxidativedeaminationofamines.Substratesincludeanumberofendogenous(內(nèi)源的)amines.第11頁(yè)/共184頁(yè)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(yè)/共184頁(yè)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(yè)/共184頁(yè)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(yè)/共184頁(yè)Table1ThedrugmetabolizingEnzymesEnzymePhaseReactionLocalicationAlcohol(醇)dehydrogenaseIOxidationCytosol(胞質(zhì)溶膠)Aldehyde(醛)dehydrogenaseIOxidationMitochondria,CytosolAldehydeoxidaseIOxidationCytosolCarbonyl(羰基)reductaseIReductionandOxidationCytosolCarboxylesterase(酯酶)IHydrolysisMicrosomes,CytosolCytochromeP450IOxidationorReductionMicrosomesDiamineoxidase(氧化酶)IOxidationMitochondria（線(xiàn)粒體）Epoxide(環(huán)氧化物)hydrolaseIHydrolysisMicrosomes,CytosolFlavin(黃素)MonooxygenaseIOxidationMicrosomes第15頁(yè)/共184頁(yè)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(yè)/共184頁(yè)Section3PhaseIBiotransformation1.Oxidations2.Reductions3.Dehalogenation4.Hydrolysis第17頁(yè)/共184頁(yè)1.OxidationsI.OxidationofcompoundscontainingCII.OxidationofcompoundscontainingNIII.O-dealkylationofethers

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

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

1.Formonosubstitutedbenzenecompounds,parahydroxylationusuallypredominates,withsomeorthoproductbeingformed.2.Incaseswherethereismorethanonephenylring,onlyoneringisusuallyhydroxylated.第21頁(yè)/共184頁(yè)P(yáng)henytoin

(苯妥英)第22頁(yè)/共184頁(yè)P(yáng)henylbutazone

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

(可樂(lè)定)第25頁(yè)/共184頁(yè)P(yáng)robenecid

(丙磺舒)第26頁(yè)/共184頁(yè)Chlorpromazine

（氯丙嗪)第27頁(yè)/共184頁(yè)Naphthalene

（萘環(huán))Naphthaleneandhalobenzenesafford1,2-dihydrodiolsandglutathioneconjugatesbecauseofastableepoxide.第28頁(yè)/共184頁(yè)P(yáng)olycyclicaromatichydrocarbons

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

Olefinicoxidationisanalogoustoaromaticoxidation,involvinganepoxideintermediate.Stableepoxidesandvicinaldihydrodiolshavebeenisolated.

第31頁(yè)/共184頁(yè)Carbamazepine

（卡馬西平）第32頁(yè)/共184頁(yè)AflatoxinB1

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

priority第34頁(yè)/共184頁(yè)AliphaficandAlicyclicHydroxylationsAlkylsidechainsCarbonsadjacenttoSP2carbon

Alicyclic

(脂環(huán)族)第35頁(yè)/共184頁(yè)SodiumValproate

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

（異戊巴比妥）第37頁(yè)/共184頁(yè)Ibuprofen

（布洛芬）

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

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

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

A.N-DealkylationB.N-Oxidation第46頁(yè)/共184頁(yè)A.N-DealkylationThemechanismfortheN-dealkylationreactionisoxidationoftheα-carbon,generatinganunstablecarbinolamine（甲醇胺）thatcollapsestoyieldtheN-dealkylatedsubstrateandthecarbonylderivativeofthesubstituent.第47頁(yè)/共184頁(yè)ClassificationofN-Dealkylation第48頁(yè)/共184頁(yè)P(yáng)ropranol（普萘洛爾）第49頁(yè)/共184頁(yè)Amphetamine（苯丙胺）第50頁(yè)/共184頁(yè)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(yè)/共184頁(yè)Katamine（氯胺酮）第52頁(yè)/共184頁(yè)Lidocaine（利多卡因）toxicity第53頁(yè)/共184頁(yè)Imipramine（丙咪嗪）Desipramine地昔帕明Imipramine第54頁(yè)/共184頁(yè)N-Isopropylmethoxamine第55頁(yè)/共184頁(yè)B.N-OxidationTertiaryaminesareoxidizedtotheN-oxides;whereassecondaryandsomeprimaryaminesareconvertedintohydroxylamines(羥胺).Theformationofhydroxylaminesmayaccountforthetoxicityofmanyaromaticamines.第56頁(yè)/共184頁(yè)FMO、CYP－450andMAON-Oxidation

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

Acetaminofluorene

(2－乙酰氨基芴)第61頁(yè)/共184頁(yè)

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

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

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

Oxisuran第76頁(yè)/共184頁(yè)V.OxidationofAlcohols

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

Methanol

dehydrogenaseformaldehyde1/6therateofethanolcatalase（過(guò)氧化氫酶）

xanthine(黃嘌呤）oxidaseEthanoldepressestherateofmethanoloxidationbyactingasacompetitivesubstrateforalcoholdehydrogenase,reducingtheformationofthetoxicmetabolite.

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

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

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

(4-硝基喹啉-1-氧化物)第91頁(yè)/共184頁(yè)Nitrobenzene

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

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

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

CCl4induceslivernecrosis(壞死),whichismediatedthroughanactivemetabolite.

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

ROCOR1ROH+R1COOH

RONO2ROH+HNO3

ROSO3HROH+H2SO4

RNHCOR1RNH2+R1COOH第104頁(yè)/共184頁(yè)Succinylcholine

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

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

50%unhydrolyzedbiotransformedproducts第108頁(yè)/共184頁(yè)AmidesaremorestabletohydrolysisthanestersProcainamide（普魯卡因胺）Procaine（普魯卡因）第109頁(yè)/共184頁(yè)P(yáng)hthalylsulfathiazole

succinylsulfathiazole第110頁(yè)/共184頁(yè)P(yáng)haseImayproduceoneormoreofthefollowingchangesDecreasedpharmacologicactivity--deactivationIncreasedpharmacologicactivity--activationIncreasedtoxicity--intoxicationAlteredpharmacologicactivity第111頁(yè)/共184頁(yè)Section4PhaseIIBiotransformationTheconjugatesaremorepolarandlesslipid-solublethantheoriginaldrugand,therefore,willresultinmorerapideliminationofthedrugfromtissues.Theconjugationmechanismsarelargelyresponsibleforthedeactivationandenhancedexcretionofmanydrugs,whichwouldotherwiseremaininthebodyandexertprolongedpharmacologicactivity.

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

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

（布洛芬）第123頁(yè)/共184頁(yè)Desipramine

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

對(duì)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(yè)/共184頁(yè)Meprobamate

（甲丙氨酯）第126頁(yè)/共184頁(yè)磺胺噻唑(Sulfathiazole)第127頁(yè)/共184頁(yè)硫醇第128頁(yè)/共184頁(yè)硫代羧酸第129頁(yè)/共184頁(yè)P(yáng)henylbutazone

(保泰松)第130頁(yè)/共184頁(yè)Sulfinpyrazone

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

(toxicity)第136頁(yè)/共184頁(yè)Salbutamol

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

(撲熱息痛)Athigherdosestherelativeamountofglucuronideincreases.第139頁(yè)/共184頁(yè)Sulfateconjugationofsomehydroxylamine(羥胺)formshepatotoxicity(肝臟毒性)andcarcinogenicity(致癌性)第140頁(yè)/共184頁(yè)3.ConjugationwithAminoAcidsGlycineisthemostcommonaminoacidthatformsconjugateswitharomatic,aryl-aliphatic(芳烷基),andheterocycliccarboxylicacids.第141頁(yè)/共184頁(yè)Theactiveformofaceticacid(CoASH)第142頁(yè)/共184頁(yè)Brompheniramine（溴苯那敏）第143頁(yè)/共184頁(yè)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(yè)/共184頁(yè)Salicylicacid（水楊酸）第145頁(yè)/共184頁(yè)4.GlutathioneConjugationGlutathione(GSH)conjugatestoelectrophilicmoietiesofdrugsortheirmetabolites.glycinecysteineglutamicacid第146頁(yè)/共184頁(yè)GlutathioneS-transferasesappeartohavetwomainrolesOneistheconjugationofpotentiallyharmfulelectrophileswiththeendogenousnucleophile,GSH,therebyprotectingothernucleophiliccentersinthecell,suchasthosethatoccurinproteinsandnucleicacids.Thesecondisameansofexcretionfortheseelectrophiles,becauseonceconjugatedwithGSH,theyareusuallyexcretedinthebileandintheurine.第147頁(yè)/共184頁(yè)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(yè)/共184頁(yè)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(yè)/共184頁(yè)Thepathwayofmercapturicacidsynthesis

mercapturicacids(硫醇尿酸)

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

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

(對(duì)氨基水楊酸）對(duì)堿性較強(qiáng)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(duì)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(yè)/共184頁(yè)Isoniazid

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

TheprocessofO-methylati