Chapter 3 Chemical Structure and Metabolism

1. Chapter 3Chemical Structure and Metabolism 第三章  化学结构与药物代谢

2. 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).

3. 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.

4. 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.

5. 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。

6. 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.

7. 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。

8. 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

9. 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)

10. 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。

11. 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.

12. 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).

13. 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。

14. 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。

15. Table 1 The drug metabolizing Enzymes

16. Table 1 The drug metabolizing Enzymes

17. Section 3 Phase I Biotransformation • 1. Oxidations • 2. Reductions • 3. Dehalogenation • 4. Hydrolysis

18. 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

19. I. Oxidation of compounds containing C • A. Aromatic hydroxylation • B. Olefinic oxidation • C. Aliphatic and alicyclic hydroxylations

20. A. Aromatic(芳香族的) Hydroxylation main CYP-450 toxicity

21. 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.

22. Phenytoin(苯妥英)

23. Phenylbutazone(保泰松) High potency Less toxicity

24. 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.

25. Clonidine(可乐定)

26. Probenecid(丙磺舒)

27. Chlorpromazine（氯丙嗪)

28. Naphthalene（萘环) • Naphthalene and halobenzenes afford 1,2-dihydrodiols and glutathione conjugates because of a stable epoxide.

29. Polycyclic aromatic hydrocarbons (carcinogenesis)

30. 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.

31. B. Olefinic(烯烃) Oxidation • Olefinic oxidation is analogous to aromatic oxidation, involving an epoxide intermediate. • Stable epoxides and vicinal dihydrodiols have been isolated.

32. Carbamazepine（卡马西平）

33. Aflatoxin B1（黄曲霉素）

34. C. Aliphafic (脂肪族) and Alicyclic (脂环族) Hydroxylations priority

35. Aliphafic and Alicyclic Hydroxylations • Alkyl side chains • Carbons adjacent to SP2 carbon • Alicyclic(脂环族)

36. Sodium Valproate（丙戊酸钠） Alkyl side chains

37. Amobarbitar（异戊巴比妥）

38. Ibuprofen（布洛芬）

39. Oxidation of C adjacent to SP2 carbon • The 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.

40. Diazepam（地西泮） α to a carbonyl Temazepam 替马西泮

41. Tolbutamide（甲苯磺丁脲） benzyl

42. Toluene benzyl

43. Pentazocin（镇痛新） allyl

44. Tetralin (1,2,3,4-tetranaphthalene) Alicyclic benzyl

45. Acetohexamide（醋磺己脲） Alicyclic

46. II. Oxidation of compounds containing N B. N-Oxidation A. N-Dealkylation

47. A. N- Dealkylation • The 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.

48. Classification of N-Dealkylation

49. Propranol（普萘洛尔）

50. Amphetamine（苯丙胺）