化學結(jié)構(gòu)和藥物代謝ChemicalStructureandMetabolism課件

Chapter3

Chemical

StructureandMetabolism第三章

化學結(jié)構(gòu)與藥物代謝

Section1IntroductionThephysicochemicalpropertiesofdrugsthatpredispose(使偏向于)themtogoodabsorption,suchaslipophilicity(親脂性),areimpediment(妨礙)totheirelimination.Asaconsequence,theeliminationofdrugsnormallyrequirestheirconversionintowatersolublecompoundsbyaprocessofmetabolism,whichenablesexcretionviaurineorfaeces(排泄物).

MetabolismMetabolismisoftenthemajorfactordefiningthepharmacokineticsofdrugs,whichinturncaninfluencetheefficacyandside-effectprothesecompounds.Thechemicalnatureandmeansofidentificationofthesebiotransformationshavebeenwellknownformanyyears,butinrecentyearsmajoradvanceshavebeenmadeintheunderstandingoftheenzymesresponsibleforthemetabolicpathways.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)化主要是官能團反應，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，如羥基、羧基、巰基和氨基。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(?；撬?,glutamine(谷氨酰胺),allofwhichincreasethewatersolubilityofthemolecule.Conjugationreactions,suchasN-acetylationofaminesandN-,O-andS-methylation,generallyresultinmorelipophilicproducts.1.CytochromeP-450enzymesystem（CYP-450）(細胞色素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，主要進行氧化反應，需要NADPH和氧分子共同參與。也能進行還原反應,將含偶氮和硝基還原成芳香伯胺。

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FlavinMonooxygenase(FMO)

(黃素單加氧酶)TheFMOaremicrosomalenzymesandmanyofthereactionstheycatalysecanalsobecatalysedbycytochromeP450.ThecommonestFMOreactionistheoxidationofnucleophilictertiaryaminestoN-oxides,althoughprimaryandsecondaryaminesandseveralsulfur-containingdrugsarealsosubstrates.FMO通常對N和S雜原子進行氧化，而不發(fā)生雜原子的脫烷基化反應。Monoamineoxidase(MAO)(單胺氧化酶)MAOisinvolvedintheoxidativedeaminationofamines.Substratesincludeanumberofendogenous(內(nèi)源的)amines.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。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。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)MonooxygenaseIOxidationMicrosomesSection3PhaseIBiotransformation1.Oxidations2.Reductions3.Dehalogenation4.Hydrolysis1.OxidationsI.OxidationofcompoundscontainingCII.OxidationofcompoundscontainingNIII.O-dealkylationofethers

IV.OxidationofcompoundscontainingSV.OxidationofalcoholandaldehydesI.OxidationofcompoundscontainingCA.AromatichydroxylationB.OlefinicoxidationC.AliphaticandalicyclichydroxylationsCharacteristicsofaromatichydroxylation(1)

1.Formonosubstitutedbenzenecompounds,parahydroxylationusuallypredominates,withsomeorthoproductbeingformed.2.Incaseswherethereismorethanonephenylring,onlyoneringisusuallyhydroxylated.Phenytoin

(苯妥英)Phenylbutazone

(保泰松)HighpotencyLesstoxicityClonidine

(可樂定)Probenecid

(丙磺舒)Polycyclicaromatichydrocarbons

(carcinogenesis)AttentionHowever,itshouldbepointedoutthatwhereothercompetitivepathwaysofbiotransformationexist,theimportanceofareneoxideformationcanbediminished.Morevulnerablesubstituentswillbemetabolizedpreferentially,thusfacilitatingexcretion.B.Olefinic(烯烴)Oxidation

Olefinicoxidationisanalogoustoaromaticoxidation,involvinganepoxideintermediate.Stableepoxidesandvicinaldihydrodiolshavebeenisolated.

Carbamazepine

（卡馬西平）AflatoxinB1

（黃曲霉素）C.Aliphafic(脂肪族)andAlicyclic(脂環(huán)族)Hydroxylations

priorityAliphaficandAlicyclicHydroxylationsAlkylsidechainsCarbonsadjacenttoSP2carbon

Alicyclic

(脂環(huán)族)SodiumValproate

（丙戊酸鈉）AlkylsidechainsAmobarbitar

（異戊巴比妥）Ibuprofen

（布洛芬）

OxidationofCadjacenttoSP2carbonThemethylenegroupsadjacenttoSP2carbongenerallyareactivatedposition,e.g.,αtoacarbonyl;αtoadoublebond(allyl,烯丙基);αtoaphenylring(benzyl).TheyareoxidizedtothehydroxymethylderivativebyCYP－450.Diazepam（地西泮）Temazepam替馬西泮αtoacarbonylTolbutamide

（甲苯磺丁脲）benzylToluenebenzylPentazocin（鎮(zhèn)痛新）allylTetralin(1,2,3,4-tetranaphthalene)AlicyclicbenzylAcetohexamide

（醋磺己脲）AlicyclicII.OxidationofcompoundscontainingN

A.N-DealkylationB.N-OxidationA.N-DealkylationThemechanismfortheN-dealkylationreactionisoxidationoftheα-carbon,generatinganunstablecarbinolamine（甲醇胺）thatcollapsestoyieldtheN-dealkylatedsubstrateandthecarbonylderivativeofthesubstituent.ClassificationofN-DealkylationPropranol（普萘洛爾）Amphetamine（苯丙胺）CharacteristicsofN-Dealkylation1.SomeoftheNsubstituentsremovedbyoxidativedealkylationaremethyl,ethyl,n-propyl,isopropyl,n-butyl,allyl,benzyl,andothershavinganα-H.2.Substituentsthataremoreresistanttodealkylationincludethetert-butyl(noα-H)andthecyclopropylmethyl.3.Ingeneral,tertiaryaminesaredealkylatedtosecondaryaminesfasterthansecondaryaminesaredealkylatedtoprimaryamines.Katamine（氯胺酮）Lidocaine（利多卡因）toxicityImipramine（丙咪嗪）Desipramine地昔帕明ImipramineN-IsopropylmethoxamineB.N-OxidationTertiaryaminesareoxidizedtotheN-oxides;whereassecondaryandsomeprimaryaminesareconvertedintohydroxylamines(羥胺).Theformationofhydroxylaminesmayaccountforthetoxicityofmanyaromaticamines.FMO、CYP－450andMAON-Oxidation

noα-hydrogenReversible可逆TertiaryaminesGuanethidine（呱乙啶）stableTertiaryaminesDapsone（氨苯砜）抗麻風藥noα-hydrogenThemechanismwhichsomearomaticprimeandsecondaryaminesoxidetoeffecttoxicity

Acetaminofluorene

(2－乙酰氨基芴)

III.O-DealkylationofethersOxidativeO-dealkylationofethersisacommonmetabolicreaction.Themajorityofethergroupsindrugmoleculesarearomaticethers.Theseethersareoxidizedbylivermicrosomaloxidases.ThemechanismofO-dealkylationThemechanismofdealkylationisanalogoustothatofN-dealkylation,oxidationoftheα-carbon,andsubsequentdecompositionoftherelativelyunstablegemdiol.Thesubstituentalkylgroupleavesasacarbonylderivative.gemdiolCodeine（可待因）Phenacetin(非那西汀)Indomethacin

（吲哚美辛）InfluencingfactorstotherateofO-dealkylation1.TherateofO-dealkylationisafunctionofchainlength,i.e.,increasingchainlengthreducestherateofdealkylation.2.Stericfactorsandringsubstituentsinfluencetherateofdealkylation,butarecomplicatedbyelectroniceffects.3.Somedrugmoleculescontainmorethanoneethergroup,inwhichcase,usuallyonlyoneetherisdealkylated.Methoxamine（甲氧明）IV.OxidationofcompoundscontainingsulfurA.S-DealkylationB.OxidativeS-DesulfurationC.S-Oxidation6-Methylmercaptopurine

(6-甲硫嘌呤)A.S-DealkylationactiveanticancerdrugCYP－450B.OxidativeS-DesulfurationC=OP=OP=SC=SThiopental(硫噴妥)S-DesulfurationMono-oxygenase殺蟲藥對硫磷S-DesulfurationMonooxygenaseC.S-OxidationThioridazine(硫利達嗪)S-OxidationHigheractivity免疫抑制劑

OxisuranV.OxidationofAlcohols

AlcoholdehydrogenaseisanNAD-specificenzymelocatedinthesolublefractionoftissuehomogenates(組織勻漿).Itexhibitsabroadspecificityforalcohols.MetabolismsofAlcoholsMostprimaryalcoholsaldehydesothersecondarytertiaryalcoholsSomesecondaryalcoholsconjugationketonesexcretionacidOxidationofethanolethanoldehydrogenaseamicrosomalenzymesystem(M.E.O.S.)2/3InintoxicationEthylaldehyde1/3OxidationofMethanol

Methanol

dehydrogenaseformaldehyde1/6therateofethanolcatalase（過氧化氫酶）

xanthine(黃嘌呤）oxidaseEthanoldepressestherateofmethanoloxidationbyactingasacompetitivesubstrateforalcoholdehydrogenase,reducingtheformationofthetoxicmetabolite.

Mefenamic（甲滅酸）XanthineoxidasealdehydeoxidasedehydrogenaseOxidationofAldehydesEndogenousaldehydesPrimaryalcoholsbiogenicaminesexogenousaldehydescarboxylicacids2.ReductionsI.CarbonylreductionII.NO2reductionIII.AzoreductionI.ReductionofketoneKetonesarestabletofurtheroxidationandconsequentlyyieldreductionproductsasmajormetabolites.alcoholsketonesdehydrogenaseAcetohexamide(醋磺己脲)S-(-)A.StereospecificS-(+)-Methadone（美沙酮）S-(-)StereospecificNaltrexone（納曲酮）

StereospecificWarfarin（華法林）R-WarfarinquickB.Stereo-selectiveII.NitroReductionNitrocompoundsarereducedtoaromaticprimaryaminesbyanitro-reductase,presumablythroughnitrosoamineandhydroxylamineintermediates.Thesereductasesarenotsolelyresponsibleforthereductionofazoandnitrocompounds,probablybecauseofreductionbythebacterialflora(細菌群落）intheanaerobic（厭氧）environmentoftheintestine.

Themechanismofnitroreduction4-Nitroquinoline-1-oxide

(4-硝基喹啉-1-氧化物)Nitrobenzene

（硝基苯）Clonazapam（氯硝西泮）III.AzoReductionAnumberofazocompoundsareconvertedtoaromaticprimaryaminesbyCYP-450,NADPH-CYP-450enzymesysteminthelivermicrosomesandbacterialreductaseintheintestine.ThemechanismofazoreductionSulfasalazine

(柳氮磺胺吡啶）3.DehalogenationOxidativedehydrohalogenation(脫鹵化氫作用)Reductivedehalogenation(還原脫鹵)Hydrolyticdehalogenation(水解脫鹵)OxidativedehydrohalogenationRCH2XRCHOR1R2CHXR1CORRCHX2RCOXCHX3XCOX

RCOCHX2RCOCOXα－HandXCYP-450Chloramphenicol（氯霉素）OxidativedehydrohalogenationCarbontetrachloride

CCl4induceslivernecrosis(壞死),whichismediatedthroughanactivemetabolite.

ReductivedehalogenationHalothane氟烷（1）OxidativedehydrohalogenationHalothane氟烷（2）4.HydrolysisIngeneral,estersandamidesarehydrolyzedbyenzymesintheblood,livermicrosomes,kidneys,andothertissues.Estersarerapidlyhydrolyzedbyesterases(酯酶).Thereactionofhydrolysis

ROCOR1ROH+R1COOH

RONO2ROH+HNO3

ROSO3HROH+H2SO4

RNHCOR1RNH2+R1COOHSuccinylcholine

（氯化琥珀膽堿）Aspirin（阿司匹林）Diphenoxylate

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

50%unhydrolyzedbiotransformedproductsAmidesaremorestabletohydrolysisthanestersProcainamide（普魯卡因胺）Procaine（普魯卡因）Phthalylsulfathiazole

succinylsulfathiazolePhaseImayproduceoneormoreofthefollowingchangesDecreasedpharmacologicactivity--deactivationIncreasedpharmacologicactivity--activationIncreasedtoxicity--intoxicationAlteredpharmacologicactivitySection4PhaseIIBiotransformationTheconjugatesaremorepolarandlesslipid-solublethantheoriginaldrugand,therefore,willresultinmorerapideliminationofthedrugfromtissues.Theconjugationmechanismsarelargelyresponsibleforthedeactivationandenhancedexcretionofmanydrugs,whichwouldotherwiseremaininthebodyandexertprolongedpharmacologicactivity.

ClassificationofPhaseII1.Glucuronicacidconjugation2.Sulfateconjugation3.Conjugationwithaminoacids4.Glutathioneconjugation5.Acetylation6.MethylationP-aminosalicylicAcetylationO-SulfateconjugationN-GlucuronicacidconjugationO-GlucuronicacidconjugationGlucuronicacidconjugationConjugationwithglycineActivatedintermediatesinPhaseIIreactionAsarule,theconjugatingintermediatedoesnotreactdirectlywiththedrug,buteitherinanactivatedformorwithanactivatedformofthedrug.Mostoftentheseactivatedintermediatesarenucleotides(核苷酸),andthereactioniscatalyzedbyspecifictransferases(轉(zhuǎn)移酶).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).UridineDiphosphateGlucuronicAcid(UDPGA)GlucuronicAcidConjugationX=-O-、-N-、-S-、-OCO-。HXRglucuronyltransferase(UDP-葡醛酸轉(zhuǎn)移酶)βwatersolubilityTheactionofglucuronidationWiththeattachmentofthehydrophiliccarbohydratemoietycontaininganionizablecarboxylgroup,alipid-solubledrugcanbeconvertedintoamorewater-solublesubstancethatispoorlyreabsorbedbytherenaltubulesandmorereadilyexcretedinbileorurine,whereitislikelytoberecognizedbythebiliaryorrenalorganicacidtransportsystems.EnterohepaticrecyclingNotallglucuronidesareexcretedbythekidneys,however;someareexcretedintothebile,andthenintotheintestines.Theenzymeβ-glucuronidase(葡糖醛酸酶),whichispresentintheintestines,maythenhydrolyzetheconjugate,releasingthedrugtobereabsorbedandenterintotheenterohepaticshunt.Thisprocessisknownasenterohepaticrecycling.Acetaminophen

(撲熱息痛)Chloramphenicol（氯霉素）Ibuprofen

（布洛芬）Desipramine

(地昔帕明)脂肪胺中堿性較強的伯胺、仲胺結(jié)合能力強，易進行軛合反應p－Aminosalicylicacid

對氨基水楊酸芳胺的反應性小，進行葡萄糖醛酸軛合反應也比較少Meprobamate

（甲丙氨酯）磺胺噻唑(Sulfathiazole)硫醇硫代羧酸Phenylbutazone

(保泰松)Sulfinpyrazone

(硫吡宗）Morphine（嗎啡）WeakopioidantagonistStrongopioidagonist2.SulfateConjugationTheformationofsulfateconjugatesisacommonbiochemicalreactionforbothendogenouscompoundsandfordrugsandotherforeigncompounds.SulfatereactionAdrugissulfatedbytransferofanactivesulfatefrom3‘-phosphoadenosine-5’-phosphosulfate(3’-磷酸腺苷-5’-磷酰硫酸，PAPS)tothedrugacceptor,thatinvolvessulfokinases(硫激酶)(orsulfotransferases).3‘-Phosphoadenosine-5’-Phospho-Sulfate(PAPS)SulfateConjugationROHR—O—SO3HR+(toxicity)ArOHAr—O—SO3HRNH2R—NHSO3HArNH2Ar—NHSO3HRR’NOHRR’NOSO3HRR’N+

(toxicity)Salbutamol

（沙丁胺醇）TheCharacteristicsofSulfateConjugationGenerally,sulfationisahighaffinity,lowcapacityprocessincontrasttoglucuronidationwhichislowaffinity,highcapacity.Thetotalpoolofsulfateisusuallylimitedandcanbereadilyexhausted.Withincreasingdosesofadrug,therefore,conjugationwithsulfatebecomesalesspredominantpathway.Acetaminophen

(撲熱息痛)Athigherdosestherelativeamountof

glucuronideincreases.Sulfateconjugationofsomehydroxylamine(羥胺)formshepatotoxicity(肝臟毒性)andcarcinogenicity(致癌性)3.ConjugationwithAminoAcidsGlycineisthemostcommonaminoacidthatformsconjugateswitharomatic,aryl-aliphatic(芳烷基),andheterocycliccarboxylicacids.Theactiveformofaceticacid(CoASH)Brompheniramine（溴苯那敏）Benzoicacid（苯甲酸）在氨基酸軛合反應中，主要是取代的苯甲酸參加反應Salicylicacid（水楊酸）4.GlutathioneConjugationGlutathione(GSH)conjugatestoelectrophilicmoietiesofdrugsortheirmetabolites.glycinecysteineglutamicacidGlutathioneS-transferasesappeartohavetwomainrolesOneistheconjugationofpotentiallyharmfulelectrophileswiththeendogenousnucleophile,GSH,therebyprotectingothernucleophiliccentersinthecell,suchasthosethatoccurinproteinsandnucleicacids.Thesecondisameansofexcretionfortheseelectrophiles,becauseonceconjugatedwithGSH,theyareusuallyexcretedinthebileandintheurine.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)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－SGCHCl3ClCOClGSCOSGThepathwayofmercapturicacidsynthesis

mercapturicacids(硫醇尿酸)

excretedMorphine（嗎啡）GSHS-alkenetransferasecatalyzestheconju-gationofGSHwithα,β-unsaturatedcarbonylcompounds,analogoustonucleophilicattackontheβ-carbonofanactivateddoublebond.Michael加成反應5.Acetylation

Conjugationreactions,suchasN-acetylationofaminesgenerallyresultinmorelipophilicproducts.AcetylCoARX=RNH2,ArNH2,aminoacid,RSO2NH2,RNHNH2,RCONHNH2Aminosalicylate

(對氨基水楊酸）對堿性較強的脂肪族伯胺和仲胺，乙?；磻ǔ］^少，即使進行結(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行乙酰化反應。Isoniazid

（異煙肼）Conjugationreaction6.MethylationMethylationisacommonbiochemicalreactionbutappearstobeofgreatersignificanceinthemetabolismofendogenouscompoundsthanfordrugsandotherforeigncompounds.Methylationdiffersfromotherconjugationprocessesinthattheproductsformedmayinsomecaseshaveasgreatorgreaterpharmacologicactivitythantheparentmolecule.TheprocessofmethylationMethylationA.O-methylationB.N-methylationC.S-methylationA.O-methylation

TheprocessofO-methylationiscatalyzedbythema