Chapter 4 drug metabolism
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Chapter 4 Drug Metabolism ( 药物代谢 ). 1.Introduction 1.1 What is drug metabolism

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Chapter 4 Drug Metabolism ( 药物代谢 )

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Chapter 4 drug metabolism

Chapter 4 Drug Metabolism(药物代谢)

Chapter 4 drug metabolism


1.1 What is drug metabolism

The enzymatic biotransformations of drugs is known as drug metabolism that is human body evolved to protect itself against low molecular weight environmental pollutants. The principal mechanism is the use of nonspecific enzymes that transform the foreign compounds (often highly nonpolar molecules) into polar molecules that are excreted by the normal bodily processes.

Chapter 4 drug metabolism

  • 1.2 Site of Drug Metabolism and First-Pass Effect

    The principal site of drug metabolism is the liver, but the kidneys, lungs, and GI tract also are important metabolic sites.

    When a drug is taken orally (the most common route of administration), it is usually absorbed through the mucousmembrane of the small intestine or from the stomach. Once out of the GI tract it is carried by the bloodstream to the liver where it is usually first metabolized. Metabolism by liver enzymes prior to the drug reaching the systemic circulation is called the presystemic or first-pass effect, which may result in complete deactivation of the drug.

Chapter 4 drug metabolism

1.3 Purpose of Drug Metabolism Studies

Drug metabolism studies are essential for evaluating the potential safety and efficacy of drugs.

Exploration of new drugs. Based on the mechanisms of biotransformation, it is possible to design new drugs with longer half-lives and fewer side-effects.

Once the metabolic products are known, it is possible to design a compound that is inactive when administered, but which utilizes the metabolic enzymes to convert it into the active form. These compounds are known as prodrugs, and are discussed in Chapter 5

Chapter 4 drug metabolism

  • 1.4 Classfication of Drug metabolism

    Drug metabolism reactions have been

    divided into two general categories, termed phase I and phase II reactions.

    Phase I transformations

    involve reactions that introduce or unmask a functional group, such as oxygenation,reduction or hydrolysis.

    Phase II transformations

    mostly generate highly polar derivatives (known as conjugates), such as glucuronides and sulfate esters, for excretion in the urine.

Chapter 4 drug metabolism

2. Phase I transformations

Phase I or functionalization reaction, include oxdative, reductive, and hydrolytic biotransformations

The purpose of these reaction is to introduce a polar functional group (e.g., OH, COOH, NH2, SH) into the xenobiotic molecule. This can be achieved by direct introduction of functional group or by modifying or “unmasking” existing functionalities

Although Phase I reaction may not produce sufficiently hydrophilic or inactive metabolites, they generally tend to provide a functional group that can undergo subsequent phase II reactions

Chapter 4 drug metabolism

2.1 Oxidative Reactions

Oxidative biotransformations processes are, by far, the most common and important in drug metabolism.

Mixed function oxidase:

molecular oxygen O2

NADPH (reduce from of nicotinamide adenosine dinucleotide phosphate)

cytochrome P450.

Chapter 4 drug metabolism

Catalytic reaction cycle involving cytochrome P-450 in oxidation


Oxidized product


CYP450 Reductase

cytochrome P-450(Fe+3)




Activated oxygen

Chromophore absorbs at 450 nm

(NADPH) CYP450 Reductase

Chapter 4 drug metabolism

The super-family of cytochrome P450 enzymes

So far, 17 families of CYPs with about 50 isoforms have been characterized in the human genome.

classification:CYP 3 A 4


Family >40% sequence-homology

sub-family>55% sequence-homology

The following families were confirmed in humans:

CYP1-5, 7, 8, 11, 17, 19, 21, 24, 26, 27, 39, 46, 51

Main CYPs concern with the metabolism of drug :

CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4

Chapter 4 drug metabolism

Classes of substrates for cytochrome P450

Functional Product

Chapter 4 drug metabolism

  • Other oxidases

  • flavin monooxygenases

  • Classes of substrates for flavin monooxygenase see next page

  • b)Monoamine oxidase

  • These enzymes exist in mitochondria(腺粒体).

  • They catalyze oxidation of amines into aldehyde and ammonia.

  • For example, degradation of


  • c) Alcohol and aldehyde oxidases


Chapter 4 drug metabolism

Classes of substrates for flavin monooxygenase

Functional Product

Chapter 4 drug metabolism

  • 1) Aromatic Hydroxylation

    There are electron-donating groups in Aromatic ring

    Oxidation take place easily at para position

Propranol(普萘洛尔) Phenformin(苯乙双胍)


Chapter 4 drug metabolism

There areelectron-withdrawing groups in Aromatic ring

Oxidation can not teak place

lower electron

Cloud Density


Higher electron

Cloud Density



Chapter 4 drug metabolism

Epoxides of aromatic compounds

代谢与毒性:亲电反应性活泼的代谢中间体 可与DNA、RNA的亲核基团以共价键结合 对机体产生毒性

Chapter 4 drug metabolism

RNA adduct with benzo(a)pyrene metabolite

Metabolic activation of polyaromatic hydrocarbons can lead to the formation of covalent adducts with RNA,

Chapter 4 drug metabolism

  • 2) Alkene Epoxidation

  • Because alkenes are more reactive than aromatic π-bonds, it is not surprising that alkenes also are metabolically epoxidized. An example of a drug that is metabolized by alkene epoxidation is the anticonvulsant agent carbamazepine

Carbamazepine (卡马西平)

Chapter 4 drug metabolism

3) Oxidations of Alkynes



Chapter 4 drug metabolism

4) Oxidation at Aliphatic and Alicyclic Carbon Atoms

Metabolic oxidation at the terminal methyl group of an aliphatic side chain is referred to as ωoxidationand oxidation at the penultimate carbon isω-1 oxidation.

a. An saturated aliphatic side chain is oxide

at both ω andω-1 oxidations.

valproic acid (丙戊酸)

b. Alicyclic carbon is oxide to the alicyclic alcohol (R=OH).


Chapter 4 drug metabolism

5) Oxidations of Carbons Adjacent to sp2 Centers

a. Allyl carbon oxidation

Pentazocin (喷他佐辛)

b. Benzyl carbon is oxide to a alcohol further to a aldehyde



Chapter 4 drug metabolism

Oxidation of ibuprofen

ω oxidations

ω-1 oxidations

benzyl carbon oxidation

Chapter 4 drug metabolism

6) Dealkylation

Dealkylations include N-, O- and S-dealkylation.



R-XH + O=CH-R’

X = O, N, S

A n dealkylation

a. N-dealkylation

Dealkylation of secondary or tertiary amines will produce primary amines

and aldehydes





Chapter 4 drug metabolism

b. O-dealkylation and S-dealkylation

Dealkylation of ethers will produce phenols

Codeine Morphine

S-dealkylation usually produces sulfhydryl group and aldehyde.



6-methylthiopurine 6-thiopurine

Chapter 4 drug metabolism

7) Oxidative Deamination

For primary aliphatic and arylalkyl amines

By CYP450 enzyme

By Flavin monooxygenase

For example, deamination of amphetamine (安非他明,苯丙胺)

Chapter 4 drug metabolism

8) N-oxidation

For secondary amines leads to a variety of N-oxygenated products. Secondary hydroxylamine formation is common, but these metabolites are susceptible to further oxidation to give nitrones

For example, N-oxidation of fenfluramine(氟苯丙胺)

tertiary amines gives chemically stable tertiary amine N-oxides that do not undergo further oxidation unlike N-oxidation of primary and secondary amines

For example, N-oxidation of chlorpheniramine(氯苯那敏,扑尔敏)

Chapter 4 drug metabolism

9) S-oxidation

For example, N-oxidation of chlorpromazine(氯丙嗪)

Chapter 4 drug metabolism

2.2 Reductions Reactions

Classes of substrates for reductive reactions

Oxidative processes are, by far, the major pathways of drug metabolism,

but reductive reactions are important for biotransformations of the functional groups listed in Table

Reductive reactions are important for the formation of hydroxyl and amino groups that render the drug more hydrophilic and set it up for phase II conjugation

Functional group Product

Chapter 4 drug metabolism

1)Carbonyl Reduction

Carbonyl reduction typically is catalyzed by aldo-keto reductases that require NADPH or NADH as the coenzyme.

It is not common, however, to observe reduction of aldehydes to alcohols. A large variety of aliphatic and aromatic ketones, however, are reduced to alcohols by NADPH-dependent ketone reductases

Stereospecific: Ketone reductases exhibit (pro-S)-hydrogen specificity.

Stereoselectivity for enantiomer substrate:

The reduction of the anticoagulant drug warfarin(抗凝药华法林 ) is selective for the R-(+)-enantiomer; reduction of the S-(−)-isomer occurs only at high substrate concentrations.

R-Warfarin is reduced in humans principally to the R,S-warfarin alcohol.

S-warfarin is metabolized mainly to 7-hydroxywarfarin (R=OH) .

Chapter 4 drug metabolism

2) Reduction for nitro or Azo compounds

These reductases mainly exist in hepatic mitochondria with NADH or NADPH as coenzyme.


尼立达唑(抗血吸虫药 )

Chapter 4 drug metabolism




Chapter 4 drug metabolism

3) Azido Reductione and Tertiary Amine Oxide Reduction

Azido to amine

Tertiary Amine to Tertiary Amine

Imipramine N-oxide

Chapter 4 drug metabolism

4) Reductive Dehalogenation

volatile anesthetic halothane (Fluothane) is metabolized by a reductive dehalogenation mechanism by cytochrome P450

Chapter 4 drug metabolism

2.3 Hydrolytic Reactions

The hydrolytic metabolism of esters and amides leads to the formation of carboxylic acids, alcohols, and amines.

A wide variety of nonspecific esterases and amidases involved in drug metabolism are found in plasma, liver, kidney, and intestine.All mammalian tissues may contribute to the hydrolysis of a drug; however, the liver, the gastrointestinal tract, and the blood are sites of greatest hydrolytic capacity.

Chapter 4 drug metabolism

Esters can be hydrolysis easily than amides

丙泮尼地 (静脉麻醉药)


Chapter 4 drug metabolism

3. Phase II Transformations:

Conjugation Reactions(结合反应)

Phase II or conjugating enzymes, in general, catalyze the attachment of small polar endogenous molecules such as glucuronic acid, sulfate, and amino acids to drugs or, more often, to metabolites arising from phase I metabolic processes. This phase II modification further deactivates the drug, changes its physicochemical properties, and produces water-soluble metabolites that are readily excreted in the urine or bile. Phase II processes such as methylation and acetylation do not yield more polar metabolites, but serve primarily to terminate or attenuate biological activity.

Chapter 4 drug metabolism

3.1 Glucuronic Acid Conjugation(葡萄糖醛酸结合)

Coenzyme form

Groups conjugated

-OH, -COOH, -NH2,

-NR2, -SH,

Uridine-5-diphospho-α-D-glucuronic acid (UDPGA)

Ransferase enzyme:

Glucueonosyl transferase (葡萄糖醛酸转移酶)

Chapter 4 drug metabolism

1) O-Glucuronide



Fenoprofen (Carboxyl)

2) N-Glucuronide



3) S-Glucuronide


Chapter 4 drug metabolism

3.2 Sulfate Conjugation

Coenzyme form

Groups conjugated

-OH, -NH2

3’ -Phosphoadenosine-5’ -phosphosulfate (PAPS)

Ransferase enzyme:




Chapter 4 drug metabolism

3.3 Amino Acid Conjugation(Glycine and glutamine)

Groups conjugated: -COOH

Coenzyme form


Chapter 4 drug metabolism

3.4 Glutathione Conjugation

Coenzyme form

Groups conjugated:

Ar-X, arene oxide, epoxide

Ransferase enzyme

Glutathione S-transferase

Glutathione (GSH)

  • 与某些有亲电倾向的药物结合形成S-取代的谷胱甘肽结合物。

  • 与带强亲电基团的结合对正常细胞中的亲核基团的物质如蛋白质、核酸等起保护作用 。

Chapter 4 drug metabolism

3.5 Acetyl Conjugation

Coenzyme form

Groups conjugated:

OH, -NH2

Ransferase enzyme


有效的解毒途径,一般药物经N-乙酰化代谢后,生成无活性或毒性较小的产物 。



Chapter 4 drug metabolism

3.6 Methyl Conjugation

Coenzyme form

Groups conjugated:

-OH, -NH2, SH,

Heterocyclic N

Ransferase enzyme


S-Adenosyl methionine (SAM)

Chapter 4 drug metabolism

Mammalian phase II conjugating agents

Chapter 4 drug metabolism

4. Factors that affect drug metabolism

4.1 Inducers

Inducers are those that promote drug metabolism in the body. Most inducers are lipophilic compounds and have no specificity in actions.

  • 苯巴比妥:催眠药

  • 作用酶:P450中的多个亚族 诱导剂。

  • 相互作用的药物:洋地黄、氯丙嗪、苯妥因、地塞米松、保泰松等

  • 结果:加速代谢,半衰期缩短

Chapter 4 drug metabolism

4.2 Inhibitors

Inhibitors are those that inhibit drug metabolism in the body. Include competitive and non-competitive inhibitors.

  • 西咪替丁:抗溃疡药

  • 作用酶: CYP2C、CYT1A2 抑制剂

  • 相互作用的药物:华法林、苯妥英钠、氨茶碱、苯巴比妥、

  • 安定、普萘洛尔等。

  • 而雷尼替丁几乎不会抑制上述酶的活性。

  • 溃疡患者在服用上述药物时,应避免使用西咪替丁。

Chapter 4 drug metabolism

4.3 Other factors

1) Species difference.

2) Sex, age, nutrition conditions have effects on drug metabolism.

3) Hepatic functions.

Chapter 4 drug metabolism

5. Application in new drug research

  • Lead discovery

  • 2) Prodrug design

  • 3) Soft drug design

Chapter 4 drug metabolism



概念:药物代谢,又称药物的生物转化,是机体在长期进化中形成的一种自我保护功能。药物分子被机体吸收后,在体内非特异性酶的作用下发生化学转化 ,使非极性分子转化成极性分子,使之易于排出体外。



Ⅰ相代谢:又称官能团化反应 包括氧化、还原、水解等化学反应,使药物分子在酶的催化下 引入或转化成一些极性较大的官能团如羟基、羧基、氨基和巯基等,代谢产物的极性增大。包括:氧化代谢、还原代谢、水解反应等。


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