药物代谢与药物代谢性相互作用
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O2
12
Nonsynthetic– 氧化反应
Distribution of CYP450 in Humans
3A4
1A2
2D6
2C19
C YP 1A2 C YP 2A6 C YP 2B6 C YP 2C 19 C YP 2C 9 C YP 2D6 C YP 2E1 C YP 3A4
2C9
13
Nonsynthetic– 氧化反应
DRUG
CYP450 Fe3+ DRUG
NADPH + H+
CYP450 Fe3+ DRUG
OH
CYP450 Fe3+ DRUG
CYP450 reductase
NADPH + H+
O
H+
e-
H2O
CYP450
Fe2+
DRUG
e-
CYP450 Fe2+
DRUG
CYP450 Fe2+
O2
DRUG
O21-
reduction
•azo reduction •nitro reduction •disulfide reduction •others
oxidoreductases reductases
hydrolysis
•esters •amides •hemiacetals,acetal s, hemiketals,
O H
N
CH3
CH2CH2CH CH2CH3 CH3
O H
N
OH CH2CH2C(CH3)2 CH2CH3
aliphatic
O N O Amobarbital
H
O
ON O H
H
N
CH2CH3
O N O Phenobarbital
O
H
O
O H
N
ON H
OH
CH2CH3 O
aromatic
H N
CH2CH3 CH(CH3)CH2CH2CH3
•dealkylations(N-, S-, P)
•deaminations
•N-, S-, P- oxidations •S-replacements •epoxidations •others
oxidoreductases
oxidases monoamine oxidases mixed function oxidases
药物代谢及其研究进展
1
1. 药物代谢部位和代谢酶 2.药物代谢类型 3. 药物经生物转化后的活性变化 4. 药物代谢研究方法 5. 中药药物代谢性相互作用
2
前言
Pharmacokinetics (药代动力学) Metabolism (药物代谢) 药代参数及其意义? CL(清除率) T1/2(消除半衰期) 药物代谢和排泄(代谢物或原药) F(生物利用度): Fg, Fh
7
2. 药物代谢类型
• Nonsynthetic reactions - Phase Ⅰ • Synthetic reactions - Phase Ⅱ
8
Nonsynthetic Reactions
oxidation
•hydroxylations
aromatic, aliphatic, nitrogen
20
Genotype-phenotype
esterases amidases peptidases lipases
ketals
hydrolases
9
Nonsynthetic– 氧化反应
hydroxylations RH + NADPH + H+ + O2
ROH + NADP+ + H2O
The folowing three reactions involve the central nerv ous system depressants known as barbiturates.
首过效应
3
Pharmacokinetic(药代动力学) A (Absorption) 吸收 D (Distribution) 分布 M (Metabolism) 代谢 E (Elimination) 消除
4
1. 药物代谢部位和代谢酶
肝脏
肝外组织：肠 肺 肾
5
1. 药物代谢部位和代谢酶
Clearance Mechanism Possible Enzymes/Proteins Involved Oxidative metabolism CYP,FMO,MAO,Mo-CO,peroxidase Hydrolytic metabolism Esterases,amidases,epoxide hydrolase
Conjugative metabolism
UGT,ST,methyltransferase,acetyltransferase
Excretion of unchanged drug
Transports
6
1. 药物代谢部位和代谢酶
Liver SER smooth endoplasmic reticulum
14
Nonsynthetic– 氧化反应
15
Nonsynthetic– 氧化反应
16
氧化反应
17
cyt c cyt b5
NADPH
FAD FMN
cyt P450
cytochrome P450 reductase
18
Nonsynthetic– 氧化反应
phenotype - variants expressed in >2% of the population
H N
CH2CH3 CH(CH3)CH2CHCH3
aliphatic
ON O
H
Pentobarbital
ON O
OH
H
10
Nonsynthetic– 氧化反应
Most prominent and important among these is the cytochrome P450 system.
consists of Cyt P 450 and Cyt P 450 reductase
1-3 proteins depending on organism and site
Fe3+
cytochrome P 450
protoporphryrin ring system 11
氧化反应
DRUG
CYP450 Fe3+
EM
percent of population
PM - poor metabolizers EM - extensive metabolizers UEM - ultra extensive metabolizers
PM UEM
rate of biotransformation
19
CYP基因多态性
O2
12
Nonsynthetic– 氧化反应
Distribution of CYP450 in Humans
3A4
1A2
2D6
2C19
C YP 1A2 C YP 2A6 C YP 2B6 C YP 2C 19 C YP 2C 9 C YP 2D6 C YP 2E1 C YP 3A4
2C9
13
Nonsynthetic– 氧化反应
DRUG
CYP450 Fe3+ DRUG
NADPH + H+
CYP450 Fe3+ DRUG
OH
CYP450 Fe3+ DRUG
CYP450 reductase
NADPH + H+
O
H+
e-
H2O
CYP450
Fe2+
DRUG
e-
CYP450 Fe2+
DRUG
CYP450 Fe2+
O2
DRUG
O21-
reduction
•azo reduction •nitro reduction •disulfide reduction •others
oxidoreductases reductases
hydrolysis
•esters •amides •hemiacetals,acetal s, hemiketals,
O H
N
CH3
CH2CH2CH CH2CH3 CH3
O H
N
OH CH2CH2C(CH3)2 CH2CH3
aliphatic
O N O Amobarbital
H
O
ON O H
H
N
CH2CH3
O N O Phenobarbital
O
H
O
O H
N
ON H
OH
CH2CH3 O
aromatic
H N
CH2CH3 CH(CH3)CH2CH2CH3
•dealkylations(N-, S-, P)
•deaminations
•N-, S-, P- oxidations •S-replacements •epoxidations •others
oxidoreductases
oxidases monoamine oxidases mixed function oxidases
药物代谢及其研究进展
1
1. 药物代谢部位和代谢酶 2.药物代谢类型 3. 药物经生物转化后的活性变化 4. 药物代谢研究方法 5. 中药药物代谢性相互作用
2
前言
Pharmacokinetics (药代动力学) Metabolism (药物代谢) 药代参数及其意义? CL(清除率) T1/2(消除半衰期) 药物代谢和排泄(代谢物或原药) F(生物利用度): Fg, Fh
7
2. 药物代谢类型
• Nonsynthetic reactions - Phase Ⅰ • Synthetic reactions - Phase Ⅱ
8
Nonsynthetic Reactions
oxidation
•hydroxylations
aromatic, aliphatic, nitrogen
20
Genotype-phenotype
esterases amidases peptidases lipases
ketals
hydrolases
9
Nonsynthetic– 氧化反应
hydroxylations RH + NADPH + H+ + O2
ROH + NADP+ + H2O
The folowing three reactions involve the central nerv ous system depressants known as barbiturates.
首过效应
3
Pharmacokinetic(药代动力学) A (Absorption) 吸收 D (Distribution) 分布 M (Metabolism) 代谢 E (Elimination) 消除
4
1. 药物代谢部位和代谢酶
肝脏
肝外组织：肠 肺 肾
5
1. 药物代谢部位和代谢酶
Clearance Mechanism Possible Enzymes/Proteins Involved Oxidative metabolism CYP,FMO,MAO,Mo-CO,peroxidase Hydrolytic metabolism Esterases,amidases,epoxide hydrolase
Conjugative metabolism
UGT,ST,methyltransferase,acetyltransferase
Excretion of unchanged drug
Transports
6
1. 药物代谢部位和代谢酶
Liver SER smooth endoplasmic reticulum
14
Nonsynthetic– 氧化反应
15
Nonsynthetic– 氧化反应
16
氧化反应
17
cyt c cyt b5
NADPH
FAD FMN
cyt P450
cytochrome P450 reductase
18
Nonsynthetic– 氧化反应
phenotype - variants expressed in >2% of the population
H N
CH2CH3 CH(CH3)CH2CHCH3
aliphatic
ON O
H
Pentobarbital
ON O
OH
H
10
Nonsynthetic– 氧化反应
Most prominent and important among these is the cytochrome P450 system.
consists of Cyt P 450 and Cyt P 450 reductase
1-3 proteins depending on organism and site
Fe3+
cytochrome P 450
protoporphryrin ring system 11
氧化反应
DRUG
CYP450 Fe3+
EM
percent of population
PM - poor metabolizers EM - extensive metabolizers UEM - ultra extensive metabolizers
PM UEM
rate of biotransformation
19
CYP基因多态性