Chapter 4 Drug Metabolism ( 药物代谢 ). 1.Introduction 1.1 What is drug metabolism
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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.
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.
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
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.
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
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)
Chromophore absorbs at 450 nm
(NADPH) CYP450 Reductase
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
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
There are electron-donating groups in Aromatic ring
Oxidation take place easily at para position
There are oxidationelectron-withdrawing groups in Aromatic ring
Oxidation can not teak place
Epoxides of aromatic compounds oxidation
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
Metabolic activation of polyaromatic hydrocarbons can lead to the formation of covalent adducts with RNA,
3) oxidationOxidations of Alkynes
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).
a. Allyl carbon oxidation
b. Benzyl carbon is oxide to a alcohol further to a aldehyde
Oxidation of ibuprofen oxidation
benzyl carbon oxidation
6) Dealkylation oxidation
Dealkylations include N-, O- and S-dealkylation.
R-XH + O=CH-R’
X = O, N, S
Dealkylation of secondary or tertiary amines will produce primary amines
b. O-dealkylation and S-dealkylation oxidation
Dealkylation of ethers will produce phenols
S-dealkylation usually produces sulfhydryl group and aldehyde.
R-S-CH3 [R-S-CH2OH] R-SH + HCHO
7) Oxidative Deamination oxidation
For primary aliphatic and arylalkyl amines
By CYP450 enzyme
By Flavin monooxygenase
For example, deamination of amphetamine (安非他明，苯丙胺）
8) N-oxidation 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）
9) S-oxidation oxidation
For example, N-oxidation of chlorpromazine(氯丙嗪）
2.2 oxidationReductions 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
1 oxidation）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) .
2) Reduction for nitro or Azo compounds oxidation
These reductases mainly exist in hepatic mitochondria with NADH or NADPH as coenzyme.
Azido to amine
Tertiary Amine to Tertiary Amine
4) Reductive Dehalogenation oxidation
volatile anesthetic halothane (Fluothane) is metabolized by a reductive dehalogenation mechanism by cytochrome P450
2.3 Hydrolytic Reactions oxidation
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.
3. Phase II Transformations: oxidation
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.
3.1 Glucuronic Acid Conjugation oxidation（葡萄糖醛酸结合）
-OH, -COOH, -NH2,
Uridine-5-diphospho-α-D-glucuronic acid (UDPGA)
Glucueonosyl transferase (葡萄糖醛酸转移酶）
3.2 Sulfate Conjugation oxidation
3’ -Phosphoadenosine-5’ -phosphosulfate (PAPS)
3.3 Amino Acid Conjugation( oxidationGlycine and glutamine)
Groups conjugated: -COOH
3.4 Glutathione Conjugation oxidation
Ar-X, arene oxide, epoxide
3.5 Acetyl Conjugation oxidation
3.6 Methyl Conjugation oxidation
-OH, -NH2, SH,
S-Adenosyl methionine (SAM)
Mammalian phase II conjugating agents oxidation
4. Factors that affect drug metabolism oxidation
Inducers are those that promote drug metabolism in the body. Most inducers are lipophilic compounds and have no specificity in actions.
4.2 Inhibitors oxidation
Inhibitors are those that inhibit drug metabolism in the body. Include competitive and non-competitive inhibitors.
4.3 Other factors oxidation
1) Species difference.
2) Sex, age, nutrition conditions have effects on drug metabolism.
3) Hepatic functions.
5. Application in new drug research oxidation
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。