Download drug metabolism

Chapter 4 Drug
Metabolism
(药物代谢)
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1.Introduction
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.
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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 mucous membrane 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.
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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 sideeffects.
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
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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.
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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
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2.1 Oxidative Reactions
Oxidative biotransformations processes are, by far, the most common and
important in drug metabolism.
RH + NADPH + H + O2
P450
ROH + NADP + H2O
Mixed function oxidase:
molecular oxygen O2
NADPH (reduce from of nicotinamide adenosine dinucleotide phosphate)
cytochrome P450.
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Catalytic reaction cycle involving cytochrome P-450 in oxidation
Oxidized
product
(substrate)
(NADPH)
CYP450
Reductase
co
cytochrome P-450(Fe+3)
[CYP450(Fe+2)][RH]
CO
Activated
oxygen
Chromophore
absorbs at 450 nm
(NADPH) CYP450 Reductase
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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
isoenzyme
Family >40%
sequencehomology
sub-family
>55% sequencehomology
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
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Metabolic Contribution
hepatic only
CYP 2C9
10%
CYP 1A2 other
2%
3%
CYP 3A4
CYP 2D6
CYP 2C9
CYP 1A2
other
CYP 3A4
55%
CYP 2D6
30%
also small intestine
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Classes of substrates for cytochrome P450
Functional
Product
R
R
OH
R'
R
O R'
R'
R
R'
ArCHR
ArCH 2R
OH
R
R
CH2R'
R
R
O
O
R
CHR'
OH
R
CH 2R'
CHR'
OH
RCHR'
RCH2R'
OH
RCH2-X-R'
(X=N,O,S,halogen)
R-X-R'
(X=NR,S)
RCH-XR'
RCHO
OH
R N R'
O
+
RXH
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Other oxidases
a) 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
RCH2-NH2
RCH=NH
RCHO + NH3
c) Alcohol and aldehyde oxidases
R-CHOH
R-CHO
R-COOH
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Classes of substrates for flavin monooxygenase
Functional
Product
R-NR'2
R-NR'2
O
R-NHR'
R-NR'
OH
R-NR'
R=NR'
OH
O
NHOH
NH
O
R-N-NHR'
R-N-NHR'
R''
R''
R-CNH2
R-CNH2
S
S
HSR
O
HNR
SH
R'HN
SO2
R'HN
2RSH
RSSR
RSSR
2RSO2
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1) Aromatic Hydroxylation
There are electron-donating groups in Aromatic ring
Oxidation take place easily at para position
NH
O
OH
N
H
N
H
R
N
H
NH
NH2
R
Propranol(普萘洛尔)
R=H
Phenformin(苯乙双胍)
R=OH
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There are electron-withdrawing groups
in Aromatic ring
O
OH
Oxidation can not teak place
CH 3
N
lower electron
Cloud Density
O S
N
O
O
Probenecid(丙磺舒)
N
Cl
Higher electron
Cloud Density
R
Diazepam
R=H
R=OH
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Epoxides of aromatic compounds
R
rearrangement
OH
R
epoxide hydrolase
H 2O
R
H
H
O
OH
R
OH
glutathione S -transf erase
GSH
OH
SG
R
macromolecular
nucleophiles X
OH
X
代谢与毒性：亲电反应性活泼的代谢中间体
亲核基团以共价键结合 对机体产生毒性
可与DNA、RNA的
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RNA adduct with benzo(a)pyrene metabolite
epoxide
hydrolase
HO
O
OH
O
N
O 10
9
HO 8
7
OH
N
R
NH
N
HO
NH
HO
OH
Metabolic activation of polyaromatic hydrocarbons can lead to the
formation of covalent adducts with RNA,
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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
HO
O
OH
epoxide
P450
hydrolase
CONH2
Carbamazepine (卡马西平)
CONH2
CONH2
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3) Oxidations of Alkynes
R C CH
O
Fe3+O
R
N
prophyrin
CYP450
CYP450
R
R C CH
Fe3+O
CYP450
COOH
R C C O
H
H
N
R
protein
O
如攻击的是端基碳，则氢原子迁移，形成烯酮，水解后生成羧酸。
如攻击的是非端位，则一酶中的卟啉的氮原子发生N-烷基化(毒性)
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4) Oxidation at Aliphatic and Alicyclic Carbon Atoms
Metabolic oxidation at the terminal methyl group of an aliphatic side chain is referred to
as ωoxidation and oxidation at the penultimate carbon isω-1 oxidation.
a. An saturated aliphatic side chain is oxide
at both ω andω-1 oxidations.
¦Ø-1
¦Ø
R
H3C
COOH
H3C
valproic acid (丙戊酸)
NH
perhexiline (R=H)
b. Alicyclic carbon is oxide to the
alicyclic alcohol (R=OH).
扩冠药哌克西林
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5) Oxidations of Carbons Adjacent to sp2 Centers
a. Allyl carbon oxidation
N
HO
CH 3
CH3
CH3
N
HO
CH3
CH3
CH 3
N
+
CH 2OH
HO
CH 3
CH3
CH 2OH
CH3
CH 3
Pentazocin (喷他佐辛）
b. Benzyl carbon is oxide to a alcohol further to a aldehyde
CH3
H3C
H
N
H
N
O
S
O O
CH2OH
H3C
H
N
H
N
O
S
O O
Tolbutamine
甲磺丁脲的氧化
O
H3C
H
N
H
N
O
S
O O
OH
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Oxidation of ibuprofen
CH3
COOH
HOH2C
CH3
COOH
H3C
H3C
ω oxidations
H3C
CH3
COOH
H 3C
H 3C
HO
CH3
Ibuprof en
COOH
H3C
H3C
ω-1 oxidations
OH
benzyl carbon
oxidation
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6) Dealkylation
Dealkylations include N-, O- and S-dealkylation.
R-X-CH2-R’
[R-X-CH(OH)-R’]
R-XH + O=CH-R’
X = O, N, S
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a. N-dealkylation
Dealkylation of secondary or tertiary amines will produce primary amines
and aldehydes
R
R
N C H
R
CH 3
R
NH
R
N C O H
R
H
N
CH 3
N
O
CH 3
CH 3
H
N
O
CH 3
CH3
O
+
CH 3
N
H
CH 3
H
N
NH2
O
CH 3
Lidocaine
N
Imipramine
Desimipramine
N
N
N
H
(去甲丙咪嗪)
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b. O-dealkylation and S-dealkylation
Dealkylation of ethers will produce phenols
N
H 3CO
N
CH 3
O
OH
O
HO
Codeine
CH 3
OH
Morphine
S-dealkylation usually produces sulfhydryl group and aldehyde.
R-S-CH3
S
[o]
CH 3
N
N
N
[R-S-CH2OH]
N
H
R-SH + HCHO
SH
N
N
N
N
H
6-methylthiopurine 6-thiopurine
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7) Oxidative Deamination
For primary aliphatic and arylalkyl amines
By CYP450 enzyme
OH
R
NH2
cytochrome
O
R
P450
R'
R
NH3
NH4
+
R'
R'
B:
H
By Flavin monooxygenase
For example, deamination
of amphetamine (安非他
明，苯丙胺）
N
a
HO
N
OH
B: b
H
NH2
flavin
monooxygenase
b
HN
OH
-H2O
b
NH
B-H
NO2
HO
N
O
N
H B:
H2O
NH2OH
+
O
OH
O
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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）
F3C
CH3
HN
F3C
CH3
F3C
CH3
HO
N
CH3
CH3
O
N
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）
Cl
Cl
N
O
N
N
N
CH3
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9) S-oxidation
R
R S O
R'
S
R'
For example, N-oxidation of chlorpromazine(氯丙嗪）
O
S
S
N
Cl
N
N
Cl
N
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2.2 Reductions Reactions
Classes of substrates for reductive reactions
Oxidative processes are, by
far, the major pathways of
drug metabolism,
Functional group
Product
O
OH
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
R
R
R'
R'
RNO 2
RNHOH
RNO
RNHOH
RNHOH
RNH 2
RN=NR'
RNH 2 + R'NH2
R3N-O
R 3N
OH
O
R
R'
R
R'
R
R'
R
R'
O
O
R-X
R + X
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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.
O
R-Warfarin is reduced in humans principally to
OH
CH3
the R,S-warfarin alcohol.

Ph
R
O
O
warfarin (R=H)
S-warfarin is metabolized mainly to 7hydroxywarfarin (R=OH) .
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2) Reduction for nitro or Azo compounds
These reductases mainly exist in hepatic mitochondria with NADH or
NADPH as coenzyme.
Nitrobenzene
2H
NO
NO2
H
N
R
2H
2H
NHOH
NH2
O
N
Cl
R
clonazepam (R=NO 2)
O
N
S
N
NH
niridazole (R=NO 2)
尼立达唑(抗血吸虫药 )
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Azo
HH
N-N
2H
N=N
2H
2
COOH
O
H
N S
O
N=N
磺胺匹林
OH
(抗结肠炎)
sulf asalazine
O
H
N S
O
COOH
NH 2
NH 2
+
H2N
OH
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3) Azido Reductione and Tertiary Amine Oxide Reduction
Azido to amine
Tertiary Amine to Tertiary Amine
O
CH3
HN
HO
O
O
N
N
O
CH 2CH2CH 2N(CH3) 2
X
zidovudine(X=N 3)
Imipramine N-oxide
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4) Reductive Dehalogenation
volatile anesthetic halothane (Fluothane) is metabolized by a reductive
dehalogenation mechanism by cytochrome P450
Br CHCF3
Cl
e
-Br
H
C CF3
Cl
escape
from
enzyme
covalent
binding
d
e
b
H C CF2
Cl F
-F
a
H
C CF3
Cl
R
RH
c
H2C CF3
Cl
ClHC CF2
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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.
O
COOH
O
CH3
O
CH 3
N
OR
H O
H
aspirin
O
cocaine (R=CH3)
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Esters can be hydrolysis easily than amides
NEt2
O
H3CO
O
O
CH3
O
Cl
O
H
N C CH 2NHC4H9
H 2N
X
NEt2
procainamide (X=NH)
procaine (X=O)
O
butanilicaine
propanidid
丙泮尼地 (静脉麻醉药)
布坦卡因
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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.
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3.1 Glucuronic Acid Conjugation（葡萄糖醛酸结合）
Coenzyme form
Groups conjugated
O
HOOC
O H
HO
O
O
HO
O
HO
O P O P
OH
-OH, -COOH, -NH2,
NH
O
N
-NR2, -SH,
O
OH
OH OH
Uridine-5-diphospho-α-D-glucuronic
acid (UDPGA)
COOH
O
Ransferase enzyme:
Glucueonosyl transferase (
葡萄糖醛酸转移酶）
OH
OH
OH
OH
H
HO
H
H
CHO
OH
H
OH
OH
COOH
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1) O-Glucuronide
OH
O 2N
H
N
CHCl2
AcHN
OH
PhO
Acetaminophen(Phenol)
OH
O
O
OH
Chloramphenicol(alcohol)
Fenoprofen (Carboxyl)
2) N-Glucuronide
OCONH 2
O
NHCH 3
Desipramine(Amine)
3) S-Glucuronide
N
SH
N
CH 3
O
NH2
Meprobamate(Amide)
（眠尔通）
Methimazole（甲巯基咪唑）
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3.2 Sulfate Conjugation
Coenzyme form
Groups conjugated
-OH, -NH2
NH2
O
O
HO S O P O
O
OH
N
N
O
3’ -Phosphoadenosine-5’ phosphosulfate (PAPS)
N
N
Ransferase enzyme:
=
O3PO
OH
Sulfotransferase
OH
H
N
H 3C
HO
HO
O
OH
CH 3
CH 3
O
S
O
Salbufamol(沙丁胺醇)
HO
HO
O
H
N
CH 3
CH 3
O
S
O
Koprenaline(异丙肾上腺素)
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3.3 Amino Acid Conjugation(Glycine and glutamine)
ATP
O
R
OH
PP i
acyl CoA synthetase
CoASH
O
R
AMP
COOH
R
H 2N
H
O
AMP
R
O
R
CoASH
SCoA
COOH
amino acid
N-acyltransf erase
R
H
N
H
Groups conjugated: -COOH
O
Coenzyme form
N
R
(Ar)
SCoA
N
H2N
+
H
N
N
O
glycine
O
n-acyltransferase
Br
Brompheniramine(溴苯那敏)
R
H
N
OH
N-oxidation
Br
COOH
Br
COOH
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3.4 Glutathione Conjugation
Coenzyme form
NH 2
HH O
N
SH
Groups conjugated:
H
O
N
H
Ar-X, arene oxide, epoxide
COOH
COOH
Ransferase enzyme
Glutathione S-transferase
Glutathione (GSH)
H 3CO2SO
SG
OSO2CH 3
H3CO 2SO
SG
S G
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 。
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3.5 Acetyl Conjugation
Coenzyme form
Groups conjugated:
OH, -NH2
O
H 3C
Ar-NH2
R-NH 2
R-OH
Ransferase enzyme
SCoA
Acetyltransferase
O
CoAS
O
CH3
O
R-O
CH 3
Ar-NH
+
Acetyl transf erase
R-SH
O
CH3
NH-R
O
R-S
CH 3
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 。
N-乙酰化转移酶的活性受遗传因素的影响较大，故有些药物的疗效、毒性和作
用时间在不同民族的人群中有种族差异。
乙酰化产物溶解度减小。
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Procainmide
O
Unchanged
in Urine, 59%
H 2N
N
N
H
24% f ast
17% slow
3%
H
Unchanged
in Urine, 85%
1%
O
N
O
NAPA
N
H
N
0.3%
H
N
O
O
N
H
H
N
O
H 2N
N
H
H
N
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3.6 Methyl Conjugation
Coenzyme form
Groups conjugated:
NH 2
N
CH3
S
HOOC
N
H
NH2
O
-OH, -NH2, SH,
Heterocyclic N
N
N
Ransferase enzyme
Methyltransferase
OH OH
S-Adenosyl methionine (SAM)
H2N
COOH
H2N
H
H2N
H3CS
COOH
H
ATP
PPi +Pi
+S
CH3
O Ad
methionine
adenosyltransferase
HO
OH
COOH
H
methyltransferase
CH3-X-R
+
S
HX-R
HO
O Ad
OH
Mammalian phase II conjugating agents
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Conjugate
Glucuronide
Coenzyme form
Groups conjugated
O
HOOC
O H
HO
O
O
HO
O
HO
O P O P
OH
OH
NH
O
N
O
Ransferase enzyme
-OH, -COOH, -NH2, UDPGlucuronosyltran
-NR2, -SH,
sferase
OH OH
Uridine-5-diphospho-α-Dglucuronic acid (UDPGA)
NH 2
Sulfate
O
O
HO S O P O
O
OH
N
N
O
H 2O3P O
N
-OH, -NH2
Sulfotransferase
-COOH
Glycine
N
OH
3-Phosphoadenosine-5phosphosulfate (PAPS)
Glycine and
glutamine
O
R
(Ar)
SCoA
+
H2N
H
COOH
R
Activated acyl or aroyl coenzyme
A cosubstrate
N-acyltransferase
Glutamine
N-acyltransferase
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Conjugate
Coenzyme form
Glutathione
NH 2
HH O
N
SH
H
O
N
H
COOH
Groups conjugated
Ransferase enzyme
Ar-X, arene oxide,
epoxide, carbocation
Glutathione
OH, -NH2
Acetyltransferase
-OH, -NH2,
Methyltransferase
S-transferase
COOH
Glutathione (GSH)
Acetyl
O
H 3C
SCoA
Acetyl coenzyme A
NH 2
Methyl
N
CH 3
S
HOOC
H
NH 2
N
O
N
N
OH OH
S-Adenosyl methionine (SAM)
SH,
Heterocyclic N
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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
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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。
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4.3 Other factors
1) Species difference.
2) Sex, age, nutrition conditions have effects on drug
metabolism.
3) Hepatic functions.
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5. Application in new drug research
1) Lead discovery
2) Prodrug design
3) Soft drug design
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本章重点内容
一、药物代谢
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。
分类：可分为Ⅰ相代谢和Ⅱ相代谢，Ⅰ相代谢又称官能团化反应，Ⅱ相代谢又
称结合反应。
药物代谢研究的目的及意义：目的是揭示药物进入人体后的结构转化及这种转
化对药物的毒性和活性的影响。研究药物代谢对新药的发现、先导化合物
的结构优化及前药的设计都具有重要意义。
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。
Ⅱ相代谢：又称结合反应，是指药物原型或经官能团化反应后产生的极性基团
与内源性的水溶性小分子如萄糖醛酸、硫酸盐、氨基酸等在酶的催化下，
以酯、酰胺或苷的形式结合，形成水溶性结合物，通过肾脏经尿排出体外。
包括与葡萄糖醛酸结合、与硫酸结合、氨基酸结合、谷胱甘肽结合等。乙
酰化和甲基化结合虽不能形成水溶性化合物，但对药物灭活起重要作用。