【正文】 但對(duì)于大多數(shù)芳香 。 HXR glucuronyl transferase (UDP葡醛酸轉(zhuǎn)移酶 ) β water solubility The action of glucuronidation ? With the attachment of the hydrophilic carbohydrate moiety containing an ionizable carboxyl group, a lipidsoluble drug can be converted into a more watersoluble 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 anic acid transport systems. Enterohepatic recycling ? Not all glucuronides are excreted by the kidneys, however。A rO 2 O 2e . _ e _.2 eA r N H 2 + A r 39。 N NA r A r 39。 R － S O 2 － R 39。 C H OHgem diol Codeine（ 可待因 ） C H 3NOC H3 O O HC H 3NOH OO HPhenacetin(非那西汀 ) C 2 H 5 O N H C O C H 3 H O N H C O C H3 a c e t a m i n o p h e n 撲 熱 息 痛Indomethacin （ 吲哚美辛 ） NCC H 3C H 2 C O O HR OOC lR = C H3R = HInfluencing factors to the rate of Odealkylation ? 1. The rate of Odealkylation is a function of chain length, ., increasing chain length reduces the rate of dealkylation. ? 2. Steric factors and ring substituents influence the rate of dealkylation, but are plicated 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） N H 2C H 3O RO C H 3O HR = C H 3R = HIV. Oxidation of pounds containing sulfur ? A. SDealkylation ? B. Oxidative SDesulfuration ? C. SOxidation 6Methylmercaptopurine (6甲硫嘌呤 ) NN NHNS C H 3NN NHNS C H 2 O HNN NHNS HA. SDealkylation active anticancer drug CYP－ 450 B. Oxidative SDesulfuration C=O P=O P=S C=S Thiopental(硫噴妥 ) H NNHC H 3OXHOX = SX = OSDesulfuration Monooxygenase 殺蟲藥對(duì)硫磷 O 2 N PSO C 2 H 5O C 2 H 5O 2 N POO C 2 H 5O C 2 H 5磷 酸 二 乙 硝 苯 酯SDesulfuration Monooxygenase C. SOxidation R － S － R 39。 R O CO HR 39。YX = S O3, A c Acetaminofluorene (2－乙酰氨基芴 ) N H C O C H 3 N C O C H3O HN C O C H 3O S O 3N C O C H 3 N H C O C H 3N u III. ODealkylation of ethers ? Oxidative Odealkylation of ethers is a mon metabolic reaction. ? The majority of ether groups in drug molecules are aromatic ethers. ? These ethers are oxidized by liver microsomal oxidases. The mechanism of Odealkylation ? The mechanism of dealkylation is analogous to that of Ndealkylation, oxidation of the αcarbon, and subsequent deposition of the relatively unstable gem diol. The substituent alkyl group leaves as a carbonyl derivative. R O C H 2 R 39。O XY O XRNR 39。HRNR 39。NRHR 39。 α to a phenyl ring (benzyl). ? They are oxidized to the hydroxymethyl derivative by CYP－ 450. Diazepam（ 地西泮 ） NNC H3OC lNNC H3OC lHO HTemazepam 替馬西泮 α to a carbonyl Tolbutamide （甲苯磺丁脲） C H 3S O 2 N H C O N H C 4 H 9C H 2 O HS O 2 N H C O N H C 4 H 9C O O HS O 2 N H C O N H C 4 H 9benzyl Toluene C H 3 C O O Hbenzyl Pentazocin（鎮(zhèn)痛新） H OC H3C H3N C H2C H = CC H3C H3H OC H3C H3N C H2C H = CC H2O HC H3H OC H3C H3N C H2C H = CC H3C H2O Hallyl Tetralin (1,2,3,4tetranaphthalene) O HO H+Alicyclic benzyl Acetohexamide （醋磺己脲） C H 3 C O S O 2 N H C O N HHC H 3 C O S O 2 N H C O N HHHO HAlicyclic II. Oxidation of pounds containing N N C HHN C HHN C HHON C HN C HN C HO HN HO+c a r b i n o l a m i n e+ α － HC Y P － 4 5 0... .A. NDealkylation B. NOxidation A. N Dealkylation ?The mechanism for the Ndealkylation reaction is oxidation of the αcarbon, generating an unstable carbinolamine（甲醇胺） that collapses to yield the Ndealkylated substrate and the carbonyl derivative of the substituent. Classification of NDealkylation Propranol（普萘洛爾） O HO NHO HO NHO HO HO NHO HOC O O HO HO HO N H2O HOC H O+ON H2+Amphetamine（苯丙胺） N H 2 OCharacteristics of NDealkylation ? 1. Some of the N substituents removed by oxidative dealkylation are methyl, ethyl, npropyl, isopropyl, nbutyl, allyl, benzyl, and others having an αH. ? 2. Substituents that are more resistant to dealkylation include the tertbutyl (no αH) 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 ） N H C H 3C lON H 2C lOLidocaine（ 利多卡因 ） N H C O C H 2 NC H 3C H 3C 2 H 5C 2 H 5N H C O C H 2 N H C 2 H 5C H 3C H 3e a s i l ytoxicity Imipramine（ 丙咪嗪 ） Desipramine 地昔帕明 N( C H2)3N R C H3C lR = C H3R = HImipramine NIsopropylmethoxamine N H RC H3O HO C H3O HR = C H ( C H3)2 N i s o p r o p y l m e t h o x a m i n eR = H M e t h o x a m i n e （ 甲 氧 明 ）B. NOxidation ? Tertiary amines are oxidized to the Noxides。 Table 1 The drug metabolizing Enzymes Enzyme Phase Reaction Localication Alcohol(醇 ) dehydrogenase I Oxidation Cytosol(胞質(zhì)溶膠 ) Aldehyde (醛 ) dehydrogenase I Oxidation Mitochondria, Cytosol Aldehyde oxidase I Oxidation Cytosol Carbonyl (羰基 ) reductase I Reduction and Oxidation Cytosol Carboxylesterase (酯酶 ) I Hydrolysis Microsomes, Cytosol Cytochrome P450 I Oxidation or Reduction Microsomes Diamine oxidase (氧化酶 ) I Oxidation Mitochondria（線粒體） Epoxide (環(huán)氧化物 ) hydrolase I Hydrolysis Microsomes, Cytosol Flavin(黃素 ) Monooxygenase I Oxidation Microsomes Table 1 The drug metabolizing Enzymes Glucuronyl transferase II Conjugation Microsomes Glutathione Stransferase II or I Conjugati