化学结构和药物代谢chemicalstructureandmetabolismppt课件

Chapter 3 Chemical Structure and Metabolism,第三章 化学结构与药物代谢,Section 1 Introduction,The 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 profile of 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.,Section 2 Enzymes for Drug Metabolism （第二节 药物代谢的酶）,The drug metabolizing enzymes are usually classified by the reactions they catalyse, as either Phase I or Phase II.,Phase I Biotransformation,Phase 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 Biotransformation,Phase 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,3. Other oxidative enzymes,Flavin monooxygenase (黄素单加氧酶) Monoamine oxidase(单胺氧化酶) Aldehyde oxidase (醛氧化酶),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.,Aldehyde oxidase,Aldehyde oxidase can oxidize a number of substituted pyrroles(吡咯), pyridines(吡啶), primidines and purines (嘌呤). And its substrates include methotrexate (甲氨蝶呤), quinidine (奎尼定) and cyclophosphamide (环磷酰胺).,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。,Esterases,Acetylcholinesterase(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 Enzymes,Table 1 The drug metabolizing Enzymes,Section 3 Phase I Biotransformation,1. Oxidations 2. Reductions 3. Dehalogenation 4. Hydrolysis,1. Oxidations,I. Oxidation of compounds containing C II. Oxidation of compounds containing N III. O-dealkylation of ethers IV. Oxidation of compounds containing S V. Oxidation of alcohol and aldehydes,I. Oxidation of compounds containing C,A. Aromatic hydroxylation B. Olefinic oxidation C. Aliphatic and alicyclic hydroxylations,A. Aromatic(芳香族的) Hydroxylation,CYP-450,toxicity,main,Characteristics 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 potency Less toxicity,Characteristics of aromatic hydroxylation (2),3. The position of hydroxylation can often be influenced by the type of substituents on the ring according to the theories of aromatic electrophilic substitution. Electrondonating substituents enhance, whereas electronwith-drawing substituents reduce or prevent hydroxylation. 4. Steric factors must also be considered, because oxidation usually occurs at the least hindered position.,Clonidine (可乐定),Probenecid (丙磺舒),Chlorpromazine （氯丙嗪),Naphthalene （萘环),Naphthalene and halobenzenes afford 1,2-dihydrodiols and glutathione conjugates because of a stable epoxide.,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,priority,Aliphafic and Alicyclic Hydroxylations,Alkyl side chains Carbons adjacent to SP2 carbon Alicyclic (脂环族),Sodium Valproate （丙戊酸钠）,Alkyl side chains,Amobarbitar （异戊巴比妥）,Ibuprofen （布洛芬）,Oxidation of C adjacent to SP2 carbon,The methylene groups adjacent to SP2 carbon generally are activated position, e.g., to a carbonyl; to a double bond (allyl,烯丙基); to a phenyl ring (benzyl). They are oxidized to the hydroxymethyl derivative by CYP450.,Diazepam（地西泮）,Temazepam 替马西泮, to a carbonyl,Tolbutamide （甲苯磺丁脲）,benzyl,Toluene,benzyl,Pentazocin（镇痛新）,allyl,Tetralin (1,2,3,4-tetranaphthalene),Alicyclic,benzyl,Acetohexamide （醋磺己脲）,Alicyclic,II. Oxidation of compounds containing N,A. N-Dealkylation,B. N-Oxidation,A. N- Dealkylation,The mechanism for the N-dealkylation reaction is oxidation of the -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-Dealkylation,Propranol（普萘洛尔）,Amphetamine（苯丙胺）,Characteristics of N-Dealkylation,1. Some of the N substituents removed by oxidative dealkylation are methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, benzyl, and others having an -H. 2. Substituents that are more resistant to dealkylation include the tert-butyl (no -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）,toxicity,Imipramine（丙咪嗪 ）,Desipramine 地昔帕明,Imipramine,N-Isopropylmethoxamine,B. N-Oxidation,Tertiary 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、CYP450 and MAO,N-Oxidation,no - hydrogen,Reversible 可逆,Tertiary amines,Guanethidine（呱乙啶）,stable,Tertiary amines,Dapsone（氨苯砜）,抗麻风药,no - hydrogen,The mechanism which some aromatic prime and secondary amines oxide to effect toxicity,Acetaminofluorene (2乙酰氨基芴),III. O-Dealkylation of ethers,Oxidative 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-dealkylation,The mechanism of dealkylation is analogous to that of N-dealkylation, oxidation of the -carbon, and subsequent decomposition of the relatively unstable gem diol. The substituent alkyl group leaves as a carbonyl derivative.,gem diol,Codeine（可待因）,Phenacetin(非那西汀),Indomethacin （吲哚美辛）,Influencing factors to the rate of O-dealkylation,1. 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 sulfur,A. S-Dealkylation B. Oxidative S-Desulfuration C. S-Oxidation,6-Methylmercaptopurine (6-甲硫嘌呤),A. S-Dealkylation,active anticancer drug,CYP450,B. Oxidative S-Desulfuration,C=O,P=O,P=S,C=S,Thiopental(硫喷妥),S-Desulfuration,Mono-oxygenase,杀虫药对硫磷,S-Desulfuration,Monooxygenase,C. S-Oxidation,Thioridazine(硫利达嗪),S-Oxidation,Higher activity,免疫抑制剂 Oxisuran,V. 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 Alcohols,Most primary alcohols,aldehydes,other secondary tertiary alcohols,Some secondary alcohols,conjugation,ketones,excretion,acid,Oxidation of ethanol,ethanol,dehydrogenase,a microsomal enzyme system (M.E.O.S.),2/3,In intoxication,Ethyl aldehyde,1/3,Oxidation of Methanol,Methanol,dehydrogenase,formaldehyde,1/6 the rate of ethanol,catalase（过氧化氢酶） xanthine(黄嘌呤）oxidase,Ethanol 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 oxidase aldehyde oxidase dehydrogenase,Oxidation of Aldehydes,Endogenous aldehydes,Primary alcohols,biogenic amines,exogenous aldehydes,carboxylic acids,2. Reductions,I. Carbonyl reduction II. NO2 reduction III. Azo reduction,I. Reduction of ketone,Ketones are stable to further oxidation and consequently yield reduction products as major metabolites.,alcohols,ketones,dehydrogenase,Acetohexamide(醋磺己脲),S-(-),A. Stereospecific,S-(+)-Methadone（美沙酮）,S-(-),Stereospecific,Naltrexone（纳曲酮）,Stereospecific,Warfarin（华法林）,R-Warfarin,quick,B. Stereo-selective,II. Nitro Reduction,Nitro 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 reduction,4-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 reduction,Sulfasalazine (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 dehydrohalogenation,RCH2X RCHO R1R2CHX R1COR RCHX2 RCOX CHX3 XCOX RCOCHX2 RCOCOX H and X,CYP-450,Chloramphenicol（氯霉素）,Oxidative dehydrohalogenation,Carbon tetrachloride,CCl4 induces liver necrosis(坏死), which is mediated through an active metabolite.,Reductive dehalogenation,Halothane 氟烷（1）,Oxidative dehydrohalogenation,Halothane 氟烷（2）,4. Hydrolysis,In 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+R1COOH,Succinylcholine （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 products,Amides are more stable to hydrolysis than esters,Procainamide（普鲁卡因胺） Procaine（普鲁卡因）,Phthalylsulfathiazole succinylsulfathiazole,Phase I may produce one or more of the following changes,Decreased pharmacologic activity-deactivation Increased pharmacologic activity-activation Increased toxicity-intoxication Altered pharmacologic activity,Section 4 Phase II Biotransformation,The 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 II,1. Glucuronic acid conjugation 2. Sulfate conjugation 3. Conjugation with amino acids 4. Glutathione conjugation 5. Acetylation 6. Methylation,P-aminosalicylic,Acetylation,O-Sulfate conjugation,N-Glucuronic acid conjugation,O-Glucuronic acid conjugation,Glucuronic acid conjugation,Conjugation with glycine,Activated intermediates in Phase II reaction,As 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 Conjugation,Glucuronide (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-D-葡糖醛酸,UDPGA).,Uridine Diphosphate Glucuronic Acid (UDPGA),Glucuronic Acid Conjugation,X=-O-、-N-、-S-、-OCO-。,HXR,glucuronyl transferase (UDP-葡醛酸转移酶),water solubility,The action of glucuronidation,With 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 recycling,Not all glucuronides are excreted by the kidneys, however; some are excreted into the bile, and then into the intestines. The enzyme -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,pAminosalicylic 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 antagonist,Strong opioid agonist,2. Sulfate Conjugation,The formation of sulfate conjugates is a common biochemical reaction for both endogenous compounds and for drugs and other foreign compounds.,Sulfate reaction,A 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 Conjugation,ROH ROSO3H R+ (toxicity) ArOH ArOSO3H RNH2 RNHSO3H ArNH2 ArNHSO3H RRNOH RRNOSO3H RRN+ (toxicity),Salbutamol （沙丁胺醇）,The Characteristics of Sulfate Conjugation,Generally, 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 Acids,Glycine 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.,glycine,cysteine,glutamic acid,Glutathione S-transferases appear to have two main roles,One 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 RSG ROH ROSO3H RSG RRNOH RRNOSO3H RRNSG RCOCl RCOSG CHCl3 C