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Chapter 3 Chemical
Structure and Metabolism
第三章
化学结构与药物代谢
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).
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.
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.
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。
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.
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 (Hemecoupled 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。
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 oxidoreductase)
 醌还原酶
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)
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。
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.
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).
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。
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。
Table 1 The drug metabolizing Enzymes
Phase
Reaction
Localication
Alcohol(醇) dehydrogenase
I
Oxidation
Cytosol(胞质溶胶)
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（线
粒体）
Epoxide (环氧化物) hydrolase
I
Hydrolysis
Microsomes,
Cytosol
Flavin(黄素) Monooxygenase
I
Oxidation
Microsomes
Enzyme
Table 1 The drug metabolizing Enzymes
Glucuronyl transferase
II
Conjugation
Microsomes
Glutathione S-transferase
II or I
Conjugation or
reduction
Cytosol, Microsomes
Monoamine (单胺) oxidase
I
Oxidation
Mitochondria
N-acetyl transferase
II
Conjugation
Mitochondria, Cytosol
Peptidase (肽酶)
I
Hydrolysis
Blood, lysosomes
(溶酶体）
Quinone (醌) oxidoreductase
I
Reduction
Cytosol
Sulfotransferase (硫转移酶)
II
Conjugation
Cytosol
Xanthine (黄嘌呤) oxidase
I
Oxidation
Cytosol
Section 3 Phase I Biotransformation
 1. Oxidations
 2. Reductions
 3. Dehalogenation
 4. Hydrolysis
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
I. Oxidation of compounds containing C
 A. Aromatic hydroxylation
 B. Olefinic oxidation
 C. Aliphatic and alicyclic hydroxylations
A. Aromatic(芳香族的) Hydroxylation
R
R
R
rearranged
H
H
-
O
R
H
H
R
O
OH
R
main
epoxide hydrase
H
H
H2 O
O
OH
OH
glutathione S-transferases
R
GSH
OH
SG
intracellular macromolecules
R
(DNA,RNA) X
toxicity
OH
X
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.
Phenytoin
(苯妥英)
HN
O
OH
HN
N
H
O
O
N
H
O
Phenylbutazone
(保泰松)
O
C4H9
N
O
N
O
C4H9
N
O
N
OH
High potency
Less toxicity
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 electronwithdrawing substituents reduce or prevent
hydroxylation.
 4. Steric factors must also be considered,
because oxidation usually occurs at the least
hindered position.
Clonidine
(可乐定)
Cl
N
N
H
Cl
HN
Probenecid
(丙磺舒)
HOOC
SO2N£¨ CH2CH2CH3£©2
Chlorpromazine
（氯丙嗪)
R
S
N
R=H
Cl
CH2CH2CH2NMe2
R=OH
Naphthalene
（萘环)
OH
OH
O
SG
OH
 Naphthalene and halobenzenes afford 1,2dihydrodiols and glutathione conjugates
because of a stable epoxide.
Polycyclic aromatic hydrocarbons
HO
O
OH
RNA
O
RNA
HO
NH
HO
HO
OH
HO
(carcinogenesis)
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.
B. Olefinic(烯烃) Oxidation
 Olefinic oxidation is analogous to aromatic
oxidation, involving an epoxide intermediate.
 Stable epoxides and vicinal dihydrodiols have
been isolated.
Carbamazepine
（卡马西平）
O
CYP-450
N
CONH2
N
CONH2
HO
OH
epoxide hydrase
N
CONH2
Aflatoxin B1
（黄曲霉素）
O
H
O
O
H
O
O
O
O
O
O
H
O
OCH3
O
H
(aflatoxin B1)
O
O
OCH3
(epoxides)
O
DNA
(carcinogenesis)
HO
DNA
O
O
OCH3
C. Aliphafic (脂肪族) and Alicyclic (脂环族)
Hydroxylations
CH2
CYP-450
.CH
CH2
CH2
OH
CYP-450
CH
priority
CH2
CYP-450
CYP-450
CH
CH2
Aliphafic and Alicyclic Hydroxylations
 Alkyl side chains
 Carbons adjacent to SP2 carbon
 Alicyclic (脂环族)
Sodium Valproate
（丙戊酸钠）
C3H7-n
¦Ø-Oxidation
HOCH2CH2CH2
C
H
C3H7-n
C3H7-n
CH3CH2CH2
C
H
COONa
COONa
HOOCCH2CH2
HO
CH3CHCH2
¦Ø-1-Oxidation
Alkyl side chains
C
H
COONa
C3H7-n
C
H
COONa
Amobarbitar
（异戊巴比妥）
O
C2H5
O
NH
NH
O
CH3
CHCH2CH2
CH3
C2H5
NH
O
O
CH3
CCH2CH2
CH3
HO
O
NH
Ibuprofen
（布洛芬）
HOCH2
CHCH2
CH3
CH3
CHCH2
CH3
COOH
CH
CH3
CH3
C-CH2
CH3
HO
COOH
CH
CH3
COOH
CH
CH3
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.
Diazepam（地西泮）
CH3
CH3
O
O
N
N
H
Cl
N
Cl
N
OH
α to a carbonyl
Temazepam
替马西泮
Tolbutamide
（甲苯磺丁脲）
benzyl
CH3
CH2OH
COOH
SO2NHCONHC4H9 SO2NHCONHC4H9 SO2NHCONHC4H9
Toluene
benzyl
CH3
COOH
Pentazocin（镇痛新）
allyl
N
CH2 CH=C
CH2OH
CH3
CH3
N
CH2 CH=C
CH3
CH3
CH3
CH3
HO
CH3
N
CH3
CH2 CH=C
HO
CH3
CH3
HO
CH2OH
Tetralin (1,2,3,4-tetranaphthalene)
Alicyclic
OH
+
OH
benzyl
Acetohexamide
（醋磺己脲）
H
CH3CO
SO2NHCONH
CH3CO
H
Alicyclic
SO2NHCONH
H
OH
II. Oxidation of compounds containing N
H
N CH
H
N CH
+
¦Á-£- H
.
.. .
N CH
N CH
CYP£- 450
O H
N CH
carbinolamine
OH
N CH
O
B. N-Oxidation
NH +
A. N-Dealkylation
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 Ndealkylated substrate and the carbonyl
derivative of the substituent.
Classification of N-Dealkylation
Propranol（普萘洛尔）
OH
O
N
H
OH
O
OH
O
NH2
O
OH
+
N
H
OH
O
OH
N
H
CHO
O
NH2
OH
+
COOH
O
OH
Amphetamine（苯丙胺）
NH2
O
Characteristics of N-Dealkylation
 1. Some of the N substituents removed by
oxidative dealkylation are methyl, ethyl, n-propyl,
isopropyl, n-butyl, allyl, benzyl, and others
having an α-H.
 2. Substituents that are more resistant to
dealkylation include the tert-butyl (no α-H) 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）
Cl
NHCH3
O
Cl
NH2
O
Lidocaine（利多卡因）
CH3
CH3
C2H5
easily
NHCOCH2N
NHCOCH2NHC2H5
C2H5
CH3
CH3
toxicity
Imipramine（丙咪嗪 ）
Cl
N
(CH2)3NRCH3
R=CH3
Imipramine
R=H
Desipramine 地昔帕明
N-Isopropylmethoxamine
OH OH
CH3
NHR
OCH3
R=CH(CH3)2 N-isopropylmethoxamine
R=H
Methoxamine £¨ ¼×ÑõÃ÷£©
B. N-Oxidation
 Tertiary amines are oxidized to the N-oxides;
 whereas secondary and some primary amines
are converted into hydroxylamines (羟胺). The
formation of hydroxylamines may account for the
toxicity of many aromatic amines.
N-Oxidation
R
CH3
CH3
N
R
CH3
N
O
Tertiary amines
CH3
R
R
N
R'
N
N
R'
H
NH2
OH
R
R
R
N
O
R
NHOH
R
N
O
FMO、CYP－450 and MAO
no αhydrogen
Reversible
可逆
RNO2
Guanethidine（呱乙啶）
N
H
N
NH2
O
N
NH
H
N
NH2
NH
Tertiary amines
stable
Dapsone（氨苯砜）
no αhydrogen
H2N
so2
抗麻风药
NH2
H2N
so2
NHOH
The mechanism which some aromatic prime and secondary
amines oxide to effect toxicity
H
N
OH
N
R'
R
R
-OXR
H
N
H
Y
R'
OX
X
N
+
R
B+
H
N
R'
B:
X=SO3-, Ac
Y-
R
Y
R'
R'
Acetaminofluorene
(2－乙酰氨基芴)
NHCOCH3
NCOCH3
OH
NCOCH3
OSO3
NCOCH3
NHCOCH3
Nu
III. O-Dealkylation of ethers
 Oxidative O-dealkylation of ethers is a common
metabolic reaction.
 The majority of ether groups in drug molecules are
aromatic ethers.
 These ethers are oxidized by liver microsomal
oxidases.
The mechanism of O-dealkylation
 The mechanism of dealkylation is analogous to that
of N-dealkylation, oxidation of the α-carbon, and
subsequent decomposition of the relatively unstable
gem diol. The substituent alkyl group leaves as a
carbonyl derivative.
R O CH2R'
.
R O CHR'
OH
RO
C
R'
H
gem diol
ROH
+ R'CHO
Codeine（可待因）
CH3
N
CH3
N
CH3O
O
OH
HO
O
OH
Phenacetin(非那西汀)
C2H5O
NHCOCH3
HO
NHCOCH3
acetaminophen
ÆËÈÈÏ¢ Í´
Indomethacin
（吲哚美辛）
RO
CH2COOH
N
C
Cl
CH3
O
R=CH3
R=H
Influencing factors to the rate of Odealkylation
 1. The rate of O-dealkylation is a function of
chain length, i.e., increasing chain length
reduces the rate of dealkylation.
 2. Steric factors and ring substituents influence
the rate of dealkylation, but are complicated 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）
OR OH
CH3
R=CH3
NH2
OCH3
R=H
IV. Oxidation of compounds containing sulfur
 A. S-Dealkylation
 B. Oxidative S-Desulfuration
 C. S-Oxidation
6-Methylmercaptopurine
(6-甲硫嘌呤)
A. S-Dealkylation
SCH2OH
SCH3
N
N
N
N
H
CYP－450
N
N
N
N
H
SH
N
N
N
N
H
active anticancer drug
B. Oxidative S-Desulfuration
C=S
C=O
P=S
P=O
Thiopental(硫喷妥)
O
HN
X
CH3
H
N
H
O
S-Desulfuration
X=S
X=O
Mono-oxygenase
杀虫药对硫磷
S-Desulfuration
S
O
OC2H5
O2N
P
OC2H5
O2N
OC2H5
P
OC2H5
Monooxygenase Á×Ëá¶þÒÒÏõ ±½õ¥
C. S-Oxidation
FMO
R£- SO£- R'
R£- S£- R'
or CYP-450
R£- SO2£- R'
Thioridazine(硫利达嗪)
S-Oxidation
S
N
S
S CH3
N
CH3
N
O
S CH3
N
CH3
mesoridazine
ÃÀË÷´ï àº
Higher activity
免疫抑制剂
Oxisuran
O
O
S
O
O
S
CH3
O
N
N
CH3
V. Oxidation of Alcohols
 Alcohol dehydrogenase is an NAD-specific
enzyme located in the soluble fraction of tissue
homogenates(组织匀浆).
 It exhibits a broad specificity for alcohols.
RCH2OH
+ NAD
RCHO
+
NADH +
H+
Metabolisms of Alcohols
Most primary
alcohols
Some secondary
alcohols
other secondary
tertiary alcohols
aldehydes
ketones
conjugation
excretion
acid
Oxidation of ethanol
2/3
dehydrogenase
ethanol
a microsomal enzyme
system (M.E.O.S.)
1/3
In intoxication
Ethyl
aldehyde
Oxidation of Methanol
1/6 the rate of ethanol
dehydrogenase
formaldehyde
Methanol
catalase（过氧化氢酶）
xanthine(黄嘌呤）oxidase
Ethanol depresses the rate of methanol oxidation by
acting as a competitive substrate for alcohol
dehydrogenase, reducing the formation of the toxic
metabolite.
Mefenamic（甲灭酸）
COOH
R=CH3
NH
CH3
R
R=COOH
Oxidation of Aldehydes
exogenous
aldehydes
Primary
alcohols
biogenic
amines
Endogenous
aldehydes
carboxylic
acids
Xanthine oxidase
aldehyde oxidase
dehydrogenase
2. Reductions
 I. Carbonyl reduction
 II. NO2 reduction
 III. Azo reduction
I. Reduction of ketone
dehydrogenase
ketones
alcohols
 Ketones are stable to further oxidation and
consequently yield reduction products as major
metabolites.
Acetohexamide(醋磺己脲)
O
H3C
H
SO2NHCONHC6H6-c
OH
H3C
SO2NHCONHC6H6-c
S-(-)
A. Stereospecific
S-(+)-Methadone（美沙酮）
H
O
C2H5
C
C
CH2
H
CH3
C
C2H5
N(CH3)2
S-(£«)-Methadone
H
C
C
CH2
C
CH3
N(CH3)2
HO
3S,6S-¦Á-(-)-methadol
Stereospecific
S-(-)
Naltrexone（纳曲酮）
HO
O
N CH2
N CH2
OH
OH
O
HO
O
OH
human
6,¦Â-hydroxynaltrexol
Stereospecific
Warfarin（华法林）
O
quick
B. Stereo-selective
OH

Ph
O
O
R-Warfarin
II. Nitro Reduction
 Nitro compounds are reduced to aromatic primary
amines by a nitro-reductase, presumably through
nitrosoamine and hydroxylamine intermediates.
 These reductases are not solely responsible for the
reduction of azo and nitro compounds, probably
because of reduction by the bacterial flora(细菌群落）
in the anaerobic（厌氧）environment of the intestine.
The mechanism of nitro reduction
e
R
NO2
.
O-
2
e+
H
R
.
2e-
_
NO2
2H+
O2
R
2e-
R
NHOH
2H+
RNH2
NO
H
N
e-
H+
R
.
O
4-Nitroquinoline-1-oxide
(4-硝基喹啉-1-氧化物)
NO2
NHOH
N
N
O
O
Hydroxylamine intermediate
(carcinogenesis and cell toxicity)
Nitrobenzene
（硝基苯）
NO2
NHOH
ÕýÌú Ѫºì µ° °×Ö¢
methemoglobin
Clonazapam（氯硝西泮）
H
N
O2N
H
N
O
H2N
N
Cl
O
N
Cl
III. Azo Reduction
 A number of azo compounds are converted to
aromatic primary amines by CYP-450, NADPHCYP-450 enzyme system in the liver
microsomes and bacterial reductase in the
intestine.
The mechanism of azo reduction
Ar
N
N
Ar'
e-
.
_
O2
Ar
N
H
N
H
Ar'
Ar
.
N
_
N
Ar'
e2H+
O2
2e-
2H+
ArNH2 + Ar'NH2
Sulfasalazine
(柳氮磺胺吡啶）
COOH
N
N
H
SO2
N
N
OH
COOH
N
N
H
SO2
NH2
+ H2N
OH
3. Dehalogenation
 Oxidative dehydrohalogenation (脱卤化氢作用)
 Reductive dehalogenation (还原脱卤)
 Hydrolytic dehalogenation(水解脱卤)
Oxidative dehydrohalogenation
CYP-450
RCH2X
R1R2CHX
RCHX2
CHX3
RCOCHX2
α－H and X
RCHO
R1COR
RCOX
XCOX
RCOCOX
Chloramphenicol（氯霉素）
Oxidative dehydrohalogenation
NHCOCCOCl
NHCOCHCl2
O2N
CHCH CH2OH
O2N
CHCH CH2OH
OH
OH
NHCOCCO
protein
O2N
CHCH CH2OH
OH
protein
Carbon tetrachloride
CCl4
CYP450
-
.CCl
4
H+
-Cl-
.
Cl C
e-
3
O2
CHCl3
:CCl3
Cl3C O
 CCl4 induces liver necrosis(坏死), which is
mediated through an active metabolite.
O.
Halothane 氟烷（1）
H
Br
H
C
CF3
e
_
Br
CF3
Cl
Cl
Reductive
dehalogenation
.C
e
RH
_
H
.
C
CF2
Cl
F
R
protein
H
protein
C
CF3
Cl
liver toxicity
H2C
Cl
CF3
_
F
_
ClHC
CF2
Halothane 氟烷（2）
Cl
F3C
Cl
H
C
Br
F3C
OH
C
_
-
Br
Br
Oxidative dehydrohalogenation
protein
CF3COCl
H2O
F3COC
protein
CF3COOH + Cl£-
4. Hydrolysis
 In general, esters and amides are hydrolyzed by
enzymes in the blood, liver microsomes, kidneys,
and other tissues.
 Esters are rapidly hydrolyzed by esterases (酯
酶).
The reaction of hydrolysis
ROCOR1
RONO2
ROSO3H
RNHCOR1
ROH+R1COOH
ROH+HNO3
ROH+H2SO4
RNH2+R1COOH
Succinylcholine
（氯化琥珀胆碱）
O
CH2COCH2CH2N+(CH3)3
CH2COCH2CH2N+(CH3)3
O
. 2Cl-
O
CH2COH
CH2COH
O
+
2 HOCH2CH2N+(CH3)3Cl-
Aspirin（阿司匹林）
OCOCH3
OH
+ CH3COOH
COOH
COOH
Diphenoxylate
（地芬诺酯）
COOH
COOC2H5
N
C
C
CH2CH2
N
C
C
CH2CH2
diphenoxylic acid
地芬诺酸
止泻作用比原药强5倍
Atropine（阿托品）
 Esters that are
sterically hindered
are more slowly
hydrolyzed and may
appear unchanged in
the urine.
CH3
N
OH
OCOCC6H5
CH2OH
50% unchanged
50% unhydrolyzed biotransformed products
Amides are more stable to hydrolysis than esters
 Procainamide（普鲁卡因胺）
H2N
CONHCH2CH2N(C2H5)2
 Procaine（普鲁卡因）
H2N
COOCH2CH2N(C2H5)2
Phthalylsulfathiazole
succinylsulfathiazole
N
N
SO2NH
RCONH
H2N
S
R=HOOCCH2CH2£- Phthalylsulfathiazole¶¡ ¶þõ£»Ç°· àç ßò
R=
COOH
succinylsulfathiazole̪ »Ç°· àç ßò
SO2NH
S
Phase I may produce one or more of the
following changes
 Decreased pharmacologic activity--deactivation
 Increased pharmacologic activity--activation
 Increased toxicity--intoxication
 Altered pharmacologic activity
Section 4 Phase II Biotransformation
 The conjugates are more polar and less lipidsoluble than the original drug and, therefore, will
result in more rapid elimination of the drug from
tissues.
 The conjugation mechanisms are largely
responsible for the deactivation and enhanced
excretion of many drugs, which would otherwise
remain in the body and exert prolonged
pharmacologic activity.
Classification of Phase II
 1. Glucuronic acid conjugation
 2. Sulfate conjugation
 3. Conjugation with amino acids
 4. Glutathione conjugation
 5. Acetylation
 6. Methylation
P-aminosalicylic
NH2
Acetylation
N-Glucuronic
acid conjugation
COOH
O-Sulfate
conjugation
O-Glucuronic
acid conjugation
OH
Glucuronic
acid conjugation
Conjugation
with glycine
Activated intermediates in Phase II reaction
 As a rule, the conjugating intermediate does not
react directly with the drug, but either in an
activated form or with an activated form of the
drug.
 Most often these activated intermediates are
nucleotides(核苷酸), and the reaction is
catalyzed by specific transferases(转移酶).
1. Glucuronic Acid Conjugation
 Glucuronide (葡萄糖醛酸) formation is one of the most
common routes of drug metabolism and accounts for a
major share of the metabolites.
 Its significance lies in the readily available supply of
glucuronic acid in liver and in the large number of
functional groups forming glucuronide conjugates.
 Invariably,
the
glucuronide
conjugates
are
pharmacologically inactive.
 The reaction involves the condensation of the drug or its
biotransformation product with the activated form of
glucuronic acid, uridine diphosphate glucuronic acid (尿
苷-5-二磷酸-α-D-葡糖醛酸,UDPGA).
Uridine Diphosphate Glucuronic Acid (UDPGA)
Glucuronic Acid Conjugation
HXR
glucuronyl transferase
(UDP-葡醛酸转移酶)
X=-O-、-N-、-S-、-OCO-。
β
water solubility
The action of glucuronidation
 With the attachment of the hydrophilic
carbohydrate moiety containing an ionizable
carboxyl group, a lipid-soluble drug can be
converted into a more water-soluble 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
organic acid transport systems.
Enterohepatic recycling
 Not all glucuronides are excreted by the kidneys,
however; some are excreted into the bile, and
then into the intestines.
 The enzyme β-glucuronidase(葡糖醛酸酶),
which is present in the intestines, may then
hydrolyze the conjugate, releasing the drug to
be reabsorbed and enter into the enterohepatic
shunt. This process is known as enterohepatic
recycling.
Acetaminophen
(扑热息痛)
HO
NHCOCH3
GluO
NHCOCH3
Chloramphenicol（氯霉素）
NHCOCHCl2
O2N
CHCH CH2OH
OH
Ibuprofen
（布洛芬）
CH3
CHCH2
CH3
COOH
CH
CH3
CH3
CHCH2
CH3
COO£- Glu
CH
CH3
Desipramine
(地昔帕明)
Cl
N
(CH2)3NHCH3
脂肪胺中碱性较强的伯胺、仲胺结合能力强，易进行轭合反应
p－Aminosalicylic acid
对氨基水杨酸
COOH
COOH
OH
NH2
OH
NH£- Glu
芳胺的反应性小，进行葡萄糖醛酸轭合反应也比较少
Meprobamate
（甲丙氨酯）
H3C
CH2OCONH2
CH3CH2CH2 C CH2OCONH2
磺胺噻唑 (Sulfathiazole)
N
H2N
SO2NH
S
硫醇
N
CH3
SH
硫代羧酸
(C2H5)2N
SH
S
Phenylbutazone
(保泰松)
Glu
O
O
C4H9
C4H9
N
O
N
Ph
Ph
N
O
N
Ph
Ph
Sulfinpyrazone
(硫吡宗）
Glu
Ph
O
S
N
O
N
Ph
Ph
Ph
O
S
N
O
N
Ph
Ph
Morphine（吗啡）
CH3
N
HO
O
Weak opioid antagonist
OH
Strong opioid agonist
2. Sulfate Conjugation
 The formation of sulfate conjugates is a common
biochemical reaction for both endogenous
compounds and for drugs and other foreign
compounds.
Sulfate reaction
 A drug is sulfated by transfer of an active sulfate
from 3‘-phospho adenosine-5’-phosphosulfate
(3’-磷酸腺苷-5’-磷酰硫酸，PAPS) to the drug
acceptor, that involves sulfokinases(硫激酶) (or
sulfotransferases).
3‘-Phosphoadenosine-5’-Phospho-Sulfate (PAPS)
NH2
N
N
O
HO
S
O
O
O
P
N
O
O
N
OH
H2O3PO
OH
Sulfate Conjugation
 ROH
 ArOH
 RNH2
 ArNH2
 RR’NOH
R—O—SO3H
Ar—O—SO3H
R—NHSO3H
Ar—NHSO3H
RR’NOSO3H
R+ (toxicity)
RR’N+
(toxicity)
Salbutamol
（沙丁胺醇）
OH
HOCH2
HO
NHC(CH3)3
The Characteristics of Sulfate Conjugation
 Generally, sulfation is a high affinity, low
capacity process in contrast to glucuronidation
which is low affinity, high capacity.
 The total pool of sulfate is usually limited and
can be readily exhausted. With increasing doses
of a drug, therefore, conjugation with sulfate
becomes a less predominant pathway.
Acetaminophen
(扑热息痛)
HO
GluO
NHCOCH3
At low doses
or new born infant HO3SO
NHCOCH3
NHCOCH3
At higher doses the relative amount of
glucuronide increases.
Sulfate conjugation of some hydroxylamine (羟胺) forms
hepatotoxicity(肝脏毒性) and carcinogenicity(致癌性)
O
HN
O
CH3
HO
N
O
CH3
O3SO
N
CH3
£- X
OC2H5
OC2H5
O
N
CH3
OC2H5
O
HN
CH3
H
X
X
OC2H5
OC2H5
3. Conjugation with Amino Acids
 Glycine is the most common amino acid that
forms conjugates with aromatic, aryl- aliphatic
(芳烷基), and heterocyclic carboxylic acids.
The active form of acetic acid(CoASH)
ATP
R
COOH
CoASH
PPi
AMP
R CO-AMP
COOH
H2N
R
CO-SCoA
R
COOH
CoASH
H
°±»ùËá-N-õ£»¯×ª ÒÆ
ø
R
CONH
R
H
Brompheniramine（溴苯那敏）
N
N
N
N(CH3)2
Br
Br
Br
N
N
NH
COOH
Br
CHO
NH2
C
O
Br
COOH
Benzoic acid（苯甲酸）
O
COOH
OH
N
H
O
ÂíÄòËá
在氨基酸轭合反应中，主要
是取代的苯甲酸参加反应
Salicylic acid （水杨酸）
OH
OH
O
OH
COOH
N
H
O
Ë®Ñîõ£¸Ê °±Ëá
4. Glutathione Conjugation
H
cysteine
H
H
N
COOH
glutamic acid
NH2
HS
O
O
N
H
COOH
glycine
Glutathione (¹Èë׸ÊëÄ, GSH)
 Glutathione (GSH) conjugates to electrophilic
moieties of drugs or their metabolites.
Glutathione S-transferases appear to have
two main roles
 One is the conjugation of potentially harmful
electrophiles with the endogenous nucleophile,
GSH, thereby protecting other nucleophilic
centers in the cell, such as those that occur in
proteins and nucleic acids.
 The second is a means of excretion for these
electrophiles, because once conjugated with
GSH, they are usually excreted in the bile and in
the urine.
Nucleophilic substitution reaction（SN2)
Glutathione S-transferases R-X-SG
R-X-Y
X=CH2,O,S Y= halides,
=sulfonate(磺酸酯)
=epoxides,
在体内清除由于代谢产生的有害的亲电性物质
GSH在体内清除由于代谢产生的有害的亲电性物质
 RX
 ROH
 RR’NOH
R－SG
R—O—SO3H
RR’NOSO3H
 RCOCl
 CHCl3
RCO－SG
ClCOCl
RSG
RR’NSG
GSCOSG
The pathway of mercapturic acid synthesis
H
H
H
N
H
COOH
NH2
HS
O
O
N
H
E£- S
O
electrophiles
COOH
NH2
O
Glutathione S-transferases
COOH
H
H
N
N
H
COOH
H
H
°±»ùËá
¦Ã
£- ¹È°±õ£°±»ùËá
NH2
NH2
E£- S
E£- S
COOH
¹Èë׸ÊëÄת ÒÆ
ø
ÒÒõ£¸¨ øA
¸¨ ø
A
N£- ÒÒõ£»¯Ã¸
O
N
H
COOH ¸Ê°±Ëá
H
E£- S
NHCOCH3
excreted
COOH
mercapturic acids (硫醇尿酸)
Morphine（吗啡）
CH3
N
CH3
N
CH3
N
SG
GS£-
HO
O
OH
HO
O
O
HO
O
O
Morphine
Michael 加成反应
 GSH S-alkenetransferase catalyzes the conjugation of GSH with α,β-unsaturated carbonyl
compounds, analogous to nucleophilic attack on
the β-carbon of an activated double bond.
5. Acetylation
 Conjugation reactions, such as N-acetylation of
amines generally result in more lipophilic
products.
Acetyl CoA
CH3COSCoA
NAT
CoASH
(N£- ÒÒõ£×ª ÒÆ
ø)
NAT£- COCH3
RX
RX=RNH2, ArNH2, amino acid,
RSO2NH2, RNHNH2, RCONHNH2
RX£- COCH3
NAT
Aminosalicylate
(对氨基水杨酸）
COOH
OH
NH2
对碱性较强的脂肪族伯胺和仲胺，乙酰化反应通常
较少，即使进行结合率也较低。但对于大多数芳香
伯胺，由于其碱性中等极易进行乙酰化反应。
Isoniazid
（异烟肼）
CONH2NH2
N
Conjugation reaction
NHOH
R
NH
R
OH
N
R
COCH3
OCOCH3
6. Methylation
 Methylation is a common biochemical reaction
but appears to be of greater significance in the
metabolism of endogenous compounds than for
drugs and other foreign compounds.
 Methylation differs from other conjugation
processes in that the products formed may in
some cases have as great or greater
pharmacologic activity than the parent molecule.
The process of methylation
H
ATP
COOH
H
PPi + Pi
CH3
H2 N
S
methionine
(µ°°±Ëá)
H2N
methyl transferases
(¼×»ùת ÒÆ
ø)
H2N
µ°°±Ëá£- ÏÙÜÕת ÒÆ
ø
H
RXH
COOH
S+
O
adenine
CH3
COOH
S
O
adenine
+ RX£- CH3
OH OH
OH OH
S-adenosylmethionine
(SÏÙÜÕµ°°±Ëá)
Methylation
 A. O-methylation
 B. N-methylation
 C. S-methylation
A. O-methylation
 The process of O-methylation is catalyzed by the
magnesium-dependent enzyme catechol-Omethyl-transferase (COMT) (specific for
catechol-like structures), which transfers a
methyl group to the meta- or less frequently to
the p-phenolic -OH of catecholamines, such as
epinephrine and norepinephrine, but does not
methylate monohydric or other dihydric（二羟基
的）phenols.
Catecholamine
R1
HO
HO
NHR2
R1=OH, R2=H, norepinephrine
R1=OH, R2=CH3, epinephrine
R1=H, R2=H, dopamine
Terbutaline （特布他林）
OH
HO
NHC(CH3)3
OH
No methylation
B. N-methylation
 The N-methylation of various amines is catalyzed
by specific enzymes.
 Phenylethanolamine (苯乙醇胺)-N-methyltransferase (PNMT) methylates a number of
endogenous and exogenous phenylethanolamines
(e.g.,norepinephrine) but does not methylate
phenylethylamines.
 Imidazole-N-methyl-transferase specifically
methylates histamine, producing the inactive
metabolite, N1-methyl-histamine.
 A nonspecific N-methyl-transferase will methylate
the tryptamines (色胺) and other endogenous and
exogenous amines, including some heterocyclic
amines, such as pyridine (吡啶).
Norepinephrine
(去甲肾上腺素)
OH
CH3O
NH2
COMT
HO
OH
HO
NH2
OH
HO
PNMT
HO
NHCH3
HO
epinephrine
(ÉöÉÏÏÙËØ)
greater activity
第五节 药物代谢在药物研究中的作用
 通过对药物代谢的研究，人们能从定性、定量及
动力学方面来了解药物在体内的活化、去活化、
解毒及产生毒性的过程。
 对于药物化学来讲，通过对药物代谢原理和规律
的认识，可以合理地设计新药，指导新药的研究
和开发。
一、寻找和发现新药
 （一）寻找和发现新的先导化合物
 （二）先导化合物的结构修饰
 （三）对新药研究的指导作用
（一）寻找和发现新的先导化合物
 先导化合物即先导物，又称原型物，是通过各种
方法和手段确定的具有某种生物活性的化学结构。
 由于存在许多其它不需要的性质（如毒性大、药
代动力学性质不合理、药效不强等），先导化合
物不能应用于临床，利用药物代谢的知识可以进
行先导化合物的结构修饰。
（二）先导化合物的结构修饰
利用药物代谢的知识进行先导物的优化
1. 药物的潜伏化
2. 软药
1. 药物潜伏化原理
 药物潜伏化原理是把有活性的药物（原药或称母
体药物）转变为非活性的化合物，后者在体内经
酶或者化学作用，生成原药，发挥药理作用，这
种非活性化合物就是潜伏化药物。
 潜伏化药物虽然本身无活性，但比原药较好的物
理学、化学或药代动力学性质。
匹氨西林（Pivampicillin）
CHCONH
NH2
S
N
O
CH3
CH3
COOR
R=H
°± ÜÐÎ÷ ÁÖ(Ampicillin)
R=CH2OCOC(CH3)3 Æ¥°± Î÷ ÁÖ(Pivampicillin)
2. 软药
 软药指一类本身有疗效或生物活性的化学实体，
当在体内起作用后，经预料的和可控制的代谢作
用，转变成无活性和无毒性的化合物。
氯化琥珀胆碱
CH2CH2CH2CH2CH2N+(CH3)3
+
. 2Br
CH2CH2CH2CH2CH2N (CH3)3
Ê®Ìþ ¼¾
ï§
硬药
长效肌肉松弛药
-
O
CH2COCH2CH2N+(CH3)3
CH2COCH2CH2N+(CH3)3
O
软药
. 2Cl-
（三）对新药研究的指导作用
 研究活性化合物的代谢
 代谢物
 药代动力学数据
 手性药物的代谢
二、优化药物的药代动力学性质
 通过修饰缩短药物的作用时间
 通过修饰延长药物的作用时间
 通过修饰提高药物的生物利用度
 指导设计适当的剂型
（一）通过修饰缩短药物的作用时间
 在某些药物的结构中引入一些在体内代谢过程中
容易被代谢的基团，从而使原有药物在体内的时
间缩短。
 这种修饰后得到的药物和原有药物相比，在治疗
作用、吸收和分布等方面没有多大差异，但由于
作用时间的改变，可以避免一些可能的副作用。
氯化琥珀胆碱
CH2CH2CH2CH2CH2N+(CH3)3
+
. 2Br
CH2CH2CH2CH2CH2N (CH3)3
Ê®Ìþ ¼¾
ï§
长效肌肉松弛药
-
O
CH2COCH2CH2N+(CH3)3
CH2COCH2CH2N+(CH3)3
O
. 2Cl-
（三）通过修饰延长药物的作用时间
 为了延长药物的作用时间，减少药物在体内被代
谢后失去活性，通常通过对其结构进行化学修饰，
引入立体位阻较大的基团或引入难于被代谢的基
团，来降低药物在体内代谢的速度。
妥卡胺
CH3
CH3
口服
NHCOCH2N(C2H5)2
NHCOCH2NHC2H5
CH3
CH3
Àû¶à ¿¨ Òò(Lidocaine)
注射
CH3
NHCOCHNH2
CH3
CH3
Í× ¿¨ °· £¨ Tocainide£©
口服抗心律失常药物
（三）通过修饰提高药物的生物利用度
 某些药物在体内易于代谢，并生成轭合物排出体
外，结果降低了药物的生物利用度。
醋酸甲地孕酮
O
CH3
O
OCOCH3
O
CH3
OCOCH3
O
CH3
醋酸甲地孕酮
口服
（四）指导设计适当的剂型
 有些口服给药的药物存在首过效应，使活性大大
下降。
 如果将口服给药改成直肠给药，可以避免“首过
效应”的发生，增加药物的活性。
镇痛药美普他酚
CH3
CH3
N
N
OGlu
OH
CH3
CH3
首过效应
三、了解药物的作用机理