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Chapter 3

Chemical Structure and Metabolism第三章 　 化学结构与药物代谢

Section 1　IntroductionThe physicochemical properties of drugs that predispose (使偏向于) them to good absorption, such as lipophilicity (亲脂性) , are impediment(妨碍) to their elimination. As a consequence, the elimination of drugs normally requires their conversion into water soluble compounds by a process of metabolism, which enables excretion via urine or faeces(排泄物).

Metabolism Metabolism is often the major factor defining the pharmacokinetics of drugs, which in turn can influence the efficacy and side-effect pro these compounds. The chemical nature and means of identification of these biotransformations have been well known for many years, but in recent years major advances have been made in the understanding of the enzymes responsible for the metabolic pathways. Phase I BiotransformationPhase I reactions introduce, or otherwise produce, a functional group (e.g. –OH, -SH, -NH2, -COOH) into the molecule. These reaction include hydrolysis (水解) , reduction (还原) and oxidation (氧化) and are performed by a wide range of enzymes. Often these Phase I reactions precede Phase II biotransformations.第I相生物转化主要是官能团反应，包括对药物分子的氧化、还原和羟化等，在药物分子中引入或暴露极性基团，如羟基、羧基、巯基和氨基。Phase II BiotransformationPhase II reactions involve the conjugation (轭合) on a suitable chemical group of the molecule (parent compound or metabolite) and many drugs contain suitable functional groups without recourse (依赖) to Phase I metabolism. Phase II reactions include conjugation with glucuronic (葡萄糖醛酸) acid, sulfate, glutathione (谷光苷肽) or amino acids (e.g. glycine (甘氨酸), taurine (牛磺酸), glutamine(谷氨酰胺), all of which increase the water solubility of the molecule. Conjugation reactions, such as N-acetylation of amines and N-, O- and S-methylation, generally result in more lipophilic products. 1. Cytochrome P-450 enzyme system（CYP-450）(细胞色素P-450酶系)Cytochrome P-450 enzyme system (CYP-450) are a group of nonspecific enzymes (Heme-coupled monooxygenases) in liver microsomes. In a another word, CYP 450 is a liver homogenate (匀浆) fraction derived from smooth endoplasmic reticulum(光滑内质网). CYP-450是一组铁原卟啉偶联单加氧酶，位于肝微粒体中，是主要的药物代谢酶系。CYP-450属于体内的氧化－还原酶，主要进行氧化反应，需要NADPH和氧分子共同参与。也能进行还原反应,将含偶氮和硝基还原成芳香伯胺。

2. Reduction enzyme system(还原酶系)CYP-450酶系（CYP-450）醛－酮还原酶(ketoreductase)：属于氧化－还原酶。需要NADPH或NADP作为辅酶。谷胱甘肽氧化还原酶(glutathione oxido- reductase) 醌还原酶Flavin Monooxygenase (FMO) (黄素单加氧酶) The FMO are microsomal enzymes and many of the reactions they catalyse can also be catalysed by cytochrome P450. The commonest FMO reaction is the oxidation of nucleophilic tertiary amines to N-oxides, although primary and secondary amines and several sulfur-containing drugs are also substrates. FMO通常对N和S杂原子进行氧化，而不发生杂原子的脱烷基化反应。 Monoamine oxidase (MAO)(单胺氧化酶)MAO is involved in the oxidative deamination of amines. Substrates include a number of endogenous(内源的) amines. Hydrolysis Esterase (酯酶) In general, esters and amides are hydrolyzed by enzymes in the blood, liver microsomes, kidneys, and other tissues. Esters are rapidly hydrolyzed by esterases. 水解酶位于血浆、肝、肾和肠中，参与酯和酰胺的水解。但酰胺较稳定而难水解。EsterasesAcetylcholinesterase(乙酰胆碱酯酶) cholinesterase (pseudocholinesterase拟胆碱酯酶) Arylesterase(芳基酯酶)Liver microsomal esterases(肝微粒体酯酶)Other unclassified liver esterases 环氧化物酶等。 Table 1 The drug metabolizing EnzymesEnzymePhaseReactionLocalicationAlcohol(醇) dehydrogenaseIOxidationCytosol(胞质溶胶)Aldehyde (醛) dehydrogenaseIOxidationMitochondria, CytosolAldehyde oxidase IOxidationCytosolCarbonyl (羰基) reductaseIReduction and OxidationCytosolCarboxylesterase (酯酶)IHydrolysisMicrosomes, CytosolCytochrome P450IOxidation or ReductionMicrosomesDiamine oxidase (氧化酶)IOxidationMitochondria（线粒体）Epoxide (环氧化物) hydrolaseIHydrolysisMicrosomes, CytosolFlavin(黄素) Monooxygenase IOxidationMicrosomesSection 3　Phase I　Biotransformation 1. Oxidations2. Reductions3. Dehalogenation4. Hydrolysis1. OxidationsI. Oxidation of compounds containing CII. Oxidation of compounds containing NIII. O-dealkylation of ethers

IV. Oxidation of compounds containing SV. Oxidation of alcohol and aldehydesI. Oxidation of compounds containing CA. Aromatic hydroxylationB. Olefinic oxidationC. Aliphatic and alicyclic hydroxylationsCharacteristics of aromatic hydroxylation (1)

1. For monosubstituted benzene compounds, para hydroxylation usually predominates, with some ortho product being formed. 2. In cases where there is more than one phenyl ring, only one ring is usually hydroxylated. Phenytoin (苯妥英)Phenylbutazone (保泰松)High　potencyLess toxicityClonidine (可乐定)Probenecid (丙磺舒)Polycyclic aromatic hydrocarbons

(carcinogenesis)Attention However, it should be pointed out that where other competitive pathways of biotransformation exist, the importance of arene oxide formation can be diminished. More vulnerable substituents will be metabolized preferentially, thus facilitating excretion. B.　Olefinic(烯烃) Oxidation

Olefinic oxidation is analogous to aromatic oxidation, involving an epoxide intermediate. Stable epoxides and vicinal dihydrodiols have been isolated.

Carbamazepine （卡马西平）Aflatoxin B1 （黄曲霉素）C. Aliphafic (脂肪族) and Alicyclic (脂环族) Hydroxylations

priorityAliphafic and Alicyclic HydroxylationsAlkyl side chainsCarbons adjacent to SP2 carbon

Alicyclic

(脂环族)Sodium Valproate （丙戊酸钠）Alkyl side chainsAmobarbitar （异戊巴比妥）Ibuprofen （布洛芬）

Oxidation of C adjacent to SP2 carbonThe methylene groups adjacent to SP2 carbon generally are activated position, e.g., α to a carbonyl; α to a double bond (allyl,烯丙基); α to a phenyl ring (benzyl). They are oxidized to the hydroxymethyl derivative by CYP－450.Diazepam（地西泮）Temazepam替马西泮α to a carbonylTolbutamide （甲苯磺丁脲）benzylToluene benzylPentazocin（镇痛新）allylTetralin (1,2,3,4-tetranaphthalene)AlicyclicbenzylAcetohexamide （醋磺己脲）AlicyclicII. Oxidation of compounds containing N

A. N-Dealkylation B. N-OxidationA. N- DealkylationThe mechanism for the N-dealkylation reaction is oxidation of the α-carbon, generating an unstable carbinolamine（甲醇胺）that collapses to yield the N-dealkylated substrate and the carbonyl derivative of the substituent. Classification of N-DealkylationPropranol（普萘洛尔）Amphetamine（苯丙胺）Characteristics of N-Dealkylation1. Some of the N substituents removed by oxidative dealkylation are methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, benzyl, and others having an α-H. 2. Substituents that are more resistant to dealkylation include the tert-butyl (no α-H) and the cyclopropylmethyl. 3. In general, tertiary amines are dealkylated to secondary amines faster than secondary amines are dealkylated to primary amines. Katamine（氯胺酮）Lidocaine（利多卡因）toxicityImipramine（丙咪嗪 ）Desipramine　地昔帕明Imipramine N-IsopropylmethoxamineB.　N-OxidationTertiary amines are oxidized to the N-oxides;whereas secondary and some primary amines are converted into hydroxylamines (羟胺). The formation of hydroxylamines may account for the toxicity of many aromatic amines.FMO、CYP－450 and MAON-Oxidation

no α-hydrogenReversible可逆Tertiary aminesGuanethidine（呱乙啶）stableTertiary aminesDapsone（氨苯砜）抗麻风药no α-hydrogenThe mechanism which some aromatic prime and secondary amines oxide to effect toxicity

Acetaminofluorene

(2－乙酰氨基芴)

III. O-Dealkylation of ethersOxidative O-dealkylation of ethers is a common metabolic reaction. The majority of ether groups in drug molecules are aromatic ethers. These ethers are oxidized by liver microsomal oxidases.The mechanism of O-dealkylationThe mechanism of dealkylation is analogous to that of N-dealkylation, oxidation of the α-carbon, and subsequent decomposition of the relatively unstable gem diol. The substituent alkyl group leaves as a carbonyl derivative.gem diolCodeine（可待因）Phenacetin(非那西汀) Indomethacin （吲哚美辛）Influencing factors to the rate of O-dealkylation1. The rate of O-dealkylation is a function of chain length, i.e., increasing chain length reduces the rate of dealkylation. 2. Steric factors and ring substituents influence the rate of dealkylation, but are complicated by electronic effects. 3. Some drug molecules contain more than one ether group, in which case, usually only one ether is dealkylated. Methoxamine （甲氧明）IV. Oxidation of compounds containing sulfurA. S-Dealkylation B. Oxidative S-DesulfurationC. S-Oxidation6-Methylmercaptopurine (6-甲硫嘌呤)A. S-Dealkylation active anticancer drug CYP－450B. Oxidative S-DesulfurationC=OP=OP=SC=SThiopental(硫喷妥)S-DesulfurationMono-oxygenase杀虫药对硫磷S-DesulfurationMonooxygenaseC. S-OxidationThioridazine(硫利达嗪)S-OxidationHigher activity免疫抑制剂 OxisuranV. Oxidation of Alcohols

Alcohol dehydrogenase is an NAD-specific enzyme located in the soluble fraction of tissue homogenates(组织匀浆). It exhibits a broad specificity for alcohols.Metabolisms of AlcoholsMost primary alcoholsaldehydesother secondarytertiary alcoholsSome secondary alcoholsconjugationketonesexcretionacidOxidation of ethanolethanoldehydrogenasea microsomal enzyme system　(M.E.O.S.)2/3In intoxicationEthylaldehyde1/3Oxidation of Methanol

Methanol

dehydrogenaseformaldehyde1/6 the rate of ethanolcatalase（过氧化氢酶）

xanthine(黄嘌呤）oxidaseEthanol depresses the rate of methanol oxidation by acting as a competitive substrate for alcohol dehydrogenase, reducing the formation of the toxic metabolite.

Mefenamic（甲灭酸）Xanthine oxidasealdehyde oxidasedehydrogenase Oxidation of AldehydesEndogenous aldehydesPrimary alcoholsbiogenic aminesexogenous aldehydescarboxylic acids2.　ReductionsI. Carbonyl reduction II. NO2 reductionIII. Azo reductionI. Reduction of ketoneKetones are stable to further oxidation and consequently yield reduction products as major metabolites.alcoholsketonesdehydrogenaseAcetohexamide(醋磺己脲)S-(-)A. StereospecificS-(+)-Methadone（美沙酮）S-(-)StereospecificNaltrexone（纳曲酮）

StereospecificWarfarin（华法林）R-WarfarinquickB. Stereo-selectiveII. Nitro ReductionNitro compounds are reduced to aromatic primary amines by a nitro-reductase, presumably through nitrosoamine and hydroxylamine intermediates. These reductases are not solely responsible for the reduction of azo and nitro compounds, probably because of reduction by the bacterial flora(细菌群落）in the anaerobic（厌氧）environment of the intestine.

The mechanism of nitro reduction4-Nitroquinoline-1-oxide (4-硝基喹啉-1-氧化物)Nitrobenzene （硝基苯）Clonazapam（氯硝西泮）III. Azo Reduction A number of azo compounds are converted to aromatic primary amines by CYP-450, NADPH-CYP-450 enzyme system in the liver microsomes and bacterial reductase in the intestine.　The mechanism of azo reductionSulfasalazine (柳氮磺胺吡啶）3. Dehalogenation Oxidative dehydrohalogenation (脱卤化氢作用)Reductive dehalogenation (还原脱卤)Hydrolytic dehalogenation(水解脱卤) Oxidative dehydrohalogenationRCH2X　　　　　　　　　 RCHOR1R2CHX　　　　　　　 R1CORRCHX2　　　　　　　　　　　　　　RCOXCHX3　　　　　　　　　　 XCOX

RCOCHX2　　　　　　 RCOCOX α－H and XCYP-450Chloramphenicol（氯霉素）Oxidative dehydrohalogenationCarbon tetrachloride

CCl4 induces liver necrosis(坏死), which is mediated through an active metabolite.

Reductive dehalogenationHalothane 氟烷（1）Oxidative dehydrohalogenationHalothane 氟烷（2）4. HydrolysisIn general, esters and amides are hydrolyzed by enzymes in the blood, liver microsomes, kidneys, and other tissues. Esters are rapidly hydrolyzed by esterases (酯酶).The reaction of hydrolysis

ROCOR1　　　　　　 ROH+R1COOH

RONO2　　　　　　　　ROH+HNO3

ROSO3H　　　　　　　ROH+H2SO4

RNHCOR1 　　　　　 RNH2+R1COOHSuccinylcholine （氯化琥珀胆碱）Aspirin（阿司匹林）Diphenoxylate （地芬诺酯）止泻作用比原药强5倍diphenoxylic acid地芬诺酸Atropine（阿托品） Esters that are sterically hindered are more slowly hydrolyzed and may appear unchanged in the urine. 　　　　　 50% unchanged

50% unhydrolyzed biotransformed productsAmides are more stable to hydrolysis than estersProcainamide（普鲁卡因胺）Procaine（普鲁卡因）Phthalylsulfathiazole succinylsulfathiazolePhase I may produce one or more of the following changesDecreased pharmacologic activity--deactivationIncreased pharmacologic activity--activationIncreased toxicity--intoxicationAltered pharmacologic activitySection 4 Phase II BiotransformationThe conjugates are more polar and less lipid-soluble than the original drug and, therefore, will result in more rapid elimination of the drug from tissues. The conjugation mechanisms are largely responsible for the deactivation and enhanced excretion of many drugs, which would otherwise remain in the body and exert prolonged pharmacologic activity.

Classification of Phase II1. Glucuronic acid conjugation2. Sulfate conjugation3. Conjugation with amino acids4. Glutathione conjugation 5. Acetylation6. MethylationP-aminosalicylicAcetylationO-Sulfate conjugationN-Glucuronic acid conjugationO-Glucuronic acid conjugationGlucuronic acid conjugationConjugation with glycineActivated intermediates in Phase II reactionAs a rule, the conjugating intermediate does not react directly with the drug, but either in an activated form or with an activated form of the drug. Most often these activated intermediates are nucleotides(核苷酸), and the reaction is catalyzed by specific transferases(转移酶).1. Glucuronic Acid ConjugationGlucuronide (葡萄糖醛酸) formation is one of the most common routes of drug metabolism and accounts for a major share of the metabolites. Its significance lies in the readily available supply of glucuronic acid in liver and in the large number of functional groups forming glucuronide conjugates. Invariably, the glucuronide conjugates are pharmacologically inactive.The reaction involves the condensation of the drug or its biotransformation product with the activated form of glucuronic acid, uridine diphosphate glucuronic acid (尿苷-5-二磷酸-α-D-葡糖醛酸,UDPGA).Uridine Diphosphate Glucuronic Acid (UDPGA)Glucuronic Acid ConjugationX=-O-、-N-、-S-、-OCO-。HXRglucuronyl transferase (UDP-葡醛酸转移酶)βwater solubilityThe action of glucuronidationWith the attachment of the hydrophilic carbohydrate moiety containing an ionizable carboxyl group, a lipid-soluble drug can be converted into a more water-soluble substance that is poorly reabsorbed by the renal tubules and more readily excreted in bile or urine, where it is likely to be recognized by the biliary or renal organic acid transport systems. Enterohepatic recyclingNot all glucuronides are excreted by the kidneys, however; some are excreted into the bile, and then into the intestines. The enzyme β-glucuronidase(葡糖醛酸酶), which is present in the intestines, may then hydrolyze the conjugate, releasing the drug to be reabsorbed and enter into the enterohepatic shunt. This process is known as enterohepatic recycling. Acetaminophen (扑热息痛)Chloramphenicol（氯霉素）Ibuprofen （布洛芬） Desipramine　 (地昔帕明)脂肪胺中碱性较强的伯胺、仲胺结合能力强，易进行轭合反应p－Aminosalicylic acid 对氨基水杨酸芳胺的反应性小，进行葡萄糖醛酸轭合反应也比较少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（吗啡）Weak opioid antagonistStrong opioid agonist2. Sulfate ConjugationThe formation of sulfate conjugates is a common biochemical reaction for both endogenous compounds and for drugs and other foreign compounds. Sulfate reactionA drug is sulfated by transfer of an active sulfate from 3‘-phospho adenosine-5’-phosphosulfate (3’-磷酸腺苷-5’-磷酰硫酸，PAPS) to the drug acceptor, that involves sulfokinases(硫激酶) (or sulfotransferases). 3‘-Phosphoadenosine-5’-Phospho-Sulfate (PAPS)Sulfate ConjugationROH　　　　　　 R—O—SO3H　　　　　 R+ (toxicity)ArOH　　　　　　 Ar—O—SO3HRNH2　　　　　　 R—NHSO3HArNH2　　　　　　 Ar—NHSO3HRR’NOH　　　　　RR’NOSO3H　　　　　 RR’N+

(toxicity)Salbutamol （沙丁胺醇）The Characteristics of　Sulfate ConjugationGenerally, sulfation is a high affinity, low capacity process in contrast to glucuronidation which is low affinity, high capacity. The total pool of sulfate is usually limited and can be readily exhausted. With increasing doses of a drug, therefore, conjugation with sulfate becomes a less predominant pathway. Acetaminophen 　　(扑热息痛)At higher doses the relative amount of

glucuronide increases.Sulfate conjugation of some hydroxylamine (羟胺) forms hepatotoxicity(肝脏毒性) and carcinogenicity(致癌性)3. Conjugation with Amino AcidsGlycine is the most common amino acid that forms conjugates with aromatic, aryl- aliphatic (芳烷基), and heterocyclic carboxylic acids. The　active form of acetic acid(CoASH) Brompheniramine（溴苯那敏）Benzoic acid（苯甲酸）在氨基酸轭合反应中，主要是取代的苯甲酸参加反应Salicylic acid （水杨酸）4. Glutathione Conjugation Glutathione (GSH) conjugates to electrophilic moieties of drugs or their metabolites. glycinecysteineglutamic acidGlutathione S-transferases appear to have two main rolesOne is the conjugation of potentially harmful electrophiles with the endogenous nucleophile, GSH, thereby protecting other nucleophilic centers in the cell, such as those that occur in proteins and nucleic acids. The second is a means of excretion for these electrophiles, because once conjugated with GSH, they are usually excreted in the bile and in the urine. Nucleophilic substitution reaction（SN2)

R-X-Y　　　　　　　　　　　　　　　　　　　 R-X-SG

X=CH2,O,S　 Y= halides, 　　　　　　　　　　　　　 =sulfonate(磺酸酯)　　　 　　　　　　　　　　　　　 =epoxides,Glutathione S-transferases在体内清除由于代谢产生的有害的亲电性物质GSH在体内清除由于代谢产生的有害的亲电性物质RX　　　　　　　R－SGROH　　　　　　R—O—SO3H　　　　　 RSGRR’NOH　　　　　RR’NOSO3H　　　　　 RR’NSGRCOCl　　　　　RCO－SGCHCl3　　　　　 ClCOCl　　　　　 GSCOSGThe　pathway of mercapturic acid synthesis

mercapturic acids (硫醇尿酸)

excretedMorphine（吗啡）GSH S-alkenetransferase catalyzes the conju-gation of GSH with α,β-unsaturated carbonyl compounds, analogous to nucleophilic attack on the β-carbon of an activated double bond.Michael 加成反应5. Acetylation

Conjugation reactions, such as N-acetylation of amines generally result in more lipophilic products.Acetyl CoARX=RNH2, ArNH2, amino acid, RSO2NH2, RNHNH2, RCONHNH2Aminosalicylate (对氨基水杨酸）对碱性较强的脂肪族伯胺和仲胺，乙酰化反应通常较少，即使进行结合率也较低。但对于大多数芳香伯胺，由于其碱性中等极易进行乙酰化反应。Isoniazid （异烟肼）Conjugation reaction6. MethylationMethylation is a common biochemical reaction but appears to be of greater significance in the metabolism of endogenous compounds than for drugs and other foreign compounds. Methylation differs from other conjugation processes in that the products formed may in some cases have as great or greater pharmacologic activity than the parent molecule.The process of methylationMethylationA. O-methylationB. N-methylationC. S-methylationA. O-methylation

The process of O-methylation is catalyzed by the ma