细胞色素P450酶与精神药物的氧化代谢
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• ondansetron, dolasetron, tropisetron, granisetron, alosetron, azasetron, palonosetron and ramosetron.
By multiple CYP
CYP2D6 dependBaidu Nhomakorabeant
Figure 6 Chemical structures of eight setrons.
Figure 3 Chemical structures of six H2-receptor antagonists.
CYP1A2: cimetidine > ranitidine = ebrotidine; CYP2D6:cimetidine > ranitidine = ebrotidine; CYP3A4: ebrotidine> cimetidine > ranitidine.
– PM的代谢缺陷属于常染色体隐性遗传
P450酶的个体和种族差异（3）
• CYP2D6和CYP2C19的遗传多态性在地理上呈现相 反分布
– CYP2D6弱代谢者在白种人中占5%～10%，在黄种人 中占1%～2%
– CYP2C19弱代谢者在白种人中占3%～5%，在黄种人
中占15%～20%
药物与P450酶的关系
• 酶的底物(substrates)
• 抑制剂(inhibitors)
• 诱导剂(inducers)
药物的手性特征
• 对映体可以由不同P450酶代谢，如华法林R-对映体 由CYP1A2代谢而S-对映体由CYP2C9代谢 • 对映体还可以具有不同程度的酶抑制作用，如氟西 汀的S-对映体对CYP2D6的抑制作用比R-对映体强 56倍
Ⅰ
Ⅰ
AUCpo(PM)/AUC po(EM), 6.0
Ⅰ
lowest potential for interactions[
Figure 2 Metabolic differences between four PPIs
1. Its PK is less dependent on CYP2C19 genotype 2. It has less interpatient variability in clearance than omeprazole. 3. Esomeprazole is cleared more slowly in vivo and has an improved oral bioavailability.
Results
1. Gastric proton pump inhibitors
• PPI (Proton pump inhibitors): Acid-related diseases ( peptic ulcer, GERD, nonsteroidal antiinflammatory drug induced gastropathy and Zollinger-Ellison syndrome. • omeprazole, lansoprazole, pantoprazole, rabeprazole , esomeprazole.
This review focuses on seven classes of drugs for gastroin- testinal diseases treatment. Aims to help clinicians realize what kind of drug has less interpatient variability in clearance, whether to perform CYP genotyping prior to the initiation of therapy. How to enhance the management of patients on polytherapy regimens.
4. Selective 5-HT3 receptor antagonists
• selective 5-HT3-receptor antagonists are currently used for chemotherapy- and radiotherapy-induced, or postoperative nausea and vomiting.
– CYP1A2 – CYP2B6 CYP2C9/10 CYP2C19
CYP2D6
– CYP3A3/4
CYP2E1
P450酶的个体和种族差异（1）
许多药物采用同一剂量个体间的血药浓 度可以相差很大，如去甲替林同一剂量血药 浓度可相差30倍，而P450酶活性的差异是决
定其差异的主要因素。
P450酶的个体和种族差异（2）
• metoclopramide, cisapride, mosapride, itopride, renzapride and domperidone
Figure 5 Chemical structures of sevenbenzamide-type gastroprokinetic agents.
metabolized by flavin-containing monooxygenase Norcisapride is a major active meta-bolite of cisapride via CYP3A4mediated N-dealkylation.
not metabolized by CYP. It is excreted via the renal route primarily unchanged.
P450酶功能
• 催化内源物质(如甾类化合物)的代谢
• 催化外源物质(如药物)的代谢
（结果对机体可能有益也可能有害）
P450酶功能与药物的关系
• P450酶的功能涉及到体内药物的氧化代谢、
生物活化和细胞毒性致活
• 氧化代谢途径包括羟化、去甲基、去烷基和 环氧化等
人体药物氧化代谢的P450酶
• 属于14族，大约510种
3、Benzamide-type gastroprokinetic agents
• Benzamide-type gastroprokinetic agents are the mainstay of therapy in disorders of gastric motility such as non-ulcer dyspepsia (NUD), GERD, gastritis, diabetic gastroparesis and functional dyspepsia.
2. Histamine H2-receptor antagonists
• Histamine H2-receptor antagonistsare clinically applied for the treatment of gastritis, gastric and duodenal ulcers. • cimetidine, ranitidine, famotidine, nizatidine, ebrotidine and roxatidine acetate.
Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions 药学部 单媛媛
P450酶分类
根据氨基酸序列相似程度分类 • 族(相似度40%)，族用阿拉伯数字，如CYP1、 CYP2等 • 亚族(55%)，亚族用大写英文字母，如CYP1A、 CYP2D等 • 具体的酶蛋白基因，用阿拉伯数字加以区分，如 CYP1A2、CYP2D6等
P450酶的体内分布
• 主要位于肝脏
• 也见于肠道、肾脏和脑内
一、P450酶的概述
P450酶命名
• 酶蛋白中所含血红素与一氧化碳结合后于可 见光450nm处有最大吸收峰而命名 • 细胞色素P450氧化酶，简称 P450酶
• Cytochrome P450, CYP
P450酶发展史
• P450酶40年前发现
• 70年代开始研究药物氧化代谢与P450酶关系
• 迄今人体已发现约50种P450酶
• To review and summarize drug metabolism and its related interactions in prescribing drugs • within the similar therapeutic or structural class for gastrointestinal disease treatment • so as to promote rational use of medicines in clinical practice.
Ⅰ. Introduction
• Efficacy、 Safety、 Sutibility、 Cost • Irrational prescient is common
Drug metabolism and its related interactions are ignored.
Drug withdrawn from US markets due to drug-drug interactions
Materials and methods
• identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006. • Relevant literature focusing on drug metabolism, metabolic interaction potentials and clinical events of adverse drug reactions and treatment failures caused by drug-drug interaction,
• 有些P450酶(如CYP2D6和CYP2C19)的活性存在二 态性分布，即遗传多态性（genetic polymorphism） • 酶活性表型(phenotype)
– 强代谢者(extensive metabolisers, EM)
– 弱代谢者(poor metabolisers, PM)
• 酶的基因型(genotype)
Drugs for gastrointestinal diseases
• Gastric proton pump inhibitors
• Histamine H2-receptor antagonists
• Benzamidetype gastroprokinetic agents
• Selective 5-HT3 receptor antagonists • Fluoroquinolones • Macrolide antibiotics • Azole antifungals
P450酶的饱和性
• 某些P450酶具有饱和性，如CYP2D6
• 具有饱和性的酶一般肝内含量较少
• 药物对具有饱和性的酶可出现竞争性抑制
Content
I. Introduction
II.
III.
Materials and methods
Results
IV. Discussion
Abstract
Figure 1 Chemical structures of five PPIs.
AUCpo(PM)/AUCpo(EM), 7.4
Lansoprazole, omeprazole and pantoprazole are primarily metabolized by CYP2C19, an isoenzyme that exhibits genetic polymorphism AUCpo(PM)/AUCpo(EM),3.7
By multiple CYP
CYP2D6 dependBaidu Nhomakorabeant
Figure 6 Chemical structures of eight setrons.
Figure 3 Chemical structures of six H2-receptor antagonists.
CYP1A2: cimetidine > ranitidine = ebrotidine; CYP2D6:cimetidine > ranitidine = ebrotidine; CYP3A4: ebrotidine> cimetidine > ranitidine.
– PM的代谢缺陷属于常染色体隐性遗传
P450酶的个体和种族差异（3）
• CYP2D6和CYP2C19的遗传多态性在地理上呈现相 反分布
– CYP2D6弱代谢者在白种人中占5%～10%，在黄种人 中占1%～2%
– CYP2C19弱代谢者在白种人中占3%～5%，在黄种人
中占15%～20%
药物与P450酶的关系
• 酶的底物(substrates)
• 抑制剂(inhibitors)
• 诱导剂(inducers)
药物的手性特征
• 对映体可以由不同P450酶代谢，如华法林R-对映体 由CYP1A2代谢而S-对映体由CYP2C9代谢 • 对映体还可以具有不同程度的酶抑制作用，如氟西 汀的S-对映体对CYP2D6的抑制作用比R-对映体强 56倍
Ⅰ
Ⅰ
AUCpo(PM)/AUC po(EM), 6.0
Ⅰ
lowest potential for interactions[
Figure 2 Metabolic differences between four PPIs
1. Its PK is less dependent on CYP2C19 genotype 2. It has less interpatient variability in clearance than omeprazole. 3. Esomeprazole is cleared more slowly in vivo and has an improved oral bioavailability.
Results
1. Gastric proton pump inhibitors
• PPI (Proton pump inhibitors): Acid-related diseases ( peptic ulcer, GERD, nonsteroidal antiinflammatory drug induced gastropathy and Zollinger-Ellison syndrome. • omeprazole, lansoprazole, pantoprazole, rabeprazole , esomeprazole.
This review focuses on seven classes of drugs for gastroin- testinal diseases treatment. Aims to help clinicians realize what kind of drug has less interpatient variability in clearance, whether to perform CYP genotyping prior to the initiation of therapy. How to enhance the management of patients on polytherapy regimens.
4. Selective 5-HT3 receptor antagonists
• selective 5-HT3-receptor antagonists are currently used for chemotherapy- and radiotherapy-induced, or postoperative nausea and vomiting.
– CYP1A2 – CYP2B6 CYP2C9/10 CYP2C19
CYP2D6
– CYP3A3/4
CYP2E1
P450酶的个体和种族差异（1）
许多药物采用同一剂量个体间的血药浓 度可以相差很大，如去甲替林同一剂量血药 浓度可相差30倍，而P450酶活性的差异是决
定其差异的主要因素。
P450酶的个体和种族差异（2）
• metoclopramide, cisapride, mosapride, itopride, renzapride and domperidone
Figure 5 Chemical structures of sevenbenzamide-type gastroprokinetic agents.
metabolized by flavin-containing monooxygenase Norcisapride is a major active meta-bolite of cisapride via CYP3A4mediated N-dealkylation.
not metabolized by CYP. It is excreted via the renal route primarily unchanged.
P450酶功能
• 催化内源物质(如甾类化合物)的代谢
• 催化外源物质(如药物)的代谢
（结果对机体可能有益也可能有害）
P450酶功能与药物的关系
• P450酶的功能涉及到体内药物的氧化代谢、
生物活化和细胞毒性致活
• 氧化代谢途径包括羟化、去甲基、去烷基和 环氧化等
人体药物氧化代谢的P450酶
• 属于14族，大约510种
3、Benzamide-type gastroprokinetic agents
• Benzamide-type gastroprokinetic agents are the mainstay of therapy in disorders of gastric motility such as non-ulcer dyspepsia (NUD), GERD, gastritis, diabetic gastroparesis and functional dyspepsia.
2. Histamine H2-receptor antagonists
• Histamine H2-receptor antagonistsare clinically applied for the treatment of gastritis, gastric and duodenal ulcers. • cimetidine, ranitidine, famotidine, nizatidine, ebrotidine and roxatidine acetate.
Rational prescription of drugs within similar therapeutic or structural class for gastrointestinal disease treatment: Drug metabolism and its related interactions 药学部 单媛媛
P450酶分类
根据氨基酸序列相似程度分类 • 族(相似度40%)，族用阿拉伯数字，如CYP1、 CYP2等 • 亚族(55%)，亚族用大写英文字母，如CYP1A、 CYP2D等 • 具体的酶蛋白基因，用阿拉伯数字加以区分，如 CYP1A2、CYP2D6等
P450酶的体内分布
• 主要位于肝脏
• 也见于肠道、肾脏和脑内
一、P450酶的概述
P450酶命名
• 酶蛋白中所含血红素与一氧化碳结合后于可 见光450nm处有最大吸收峰而命名 • 细胞色素P450氧化酶，简称 P450酶
• Cytochrome P450, CYP
P450酶发展史
• P450酶40年前发现
• 70年代开始研究药物氧化代谢与P450酶关系
• 迄今人体已发现约50种P450酶
• To review and summarize drug metabolism and its related interactions in prescribing drugs • within the similar therapeutic or structural class for gastrointestinal disease treatment • so as to promote rational use of medicines in clinical practice.
Ⅰ. Introduction
• Efficacy、 Safety、 Sutibility、 Cost • Irrational prescient is common
Drug metabolism and its related interactions are ignored.
Drug withdrawn from US markets due to drug-drug interactions
Materials and methods
• identified by performing MEDLINE/Pubmed searches covering the period from 1988 to 2006. • Relevant literature focusing on drug metabolism, metabolic interaction potentials and clinical events of adverse drug reactions and treatment failures caused by drug-drug interaction,
• 有些P450酶(如CYP2D6和CYP2C19)的活性存在二 态性分布，即遗传多态性（genetic polymorphism） • 酶活性表型(phenotype)
– 强代谢者(extensive metabolisers, EM)
– 弱代谢者(poor metabolisers, PM)
• 酶的基因型(genotype)
Drugs for gastrointestinal diseases
• Gastric proton pump inhibitors
• Histamine H2-receptor antagonists
• Benzamidetype gastroprokinetic agents
• Selective 5-HT3 receptor antagonists • Fluoroquinolones • Macrolide antibiotics • Azole antifungals
P450酶的饱和性
• 某些P450酶具有饱和性，如CYP2D6
• 具有饱和性的酶一般肝内含量较少
• 药物对具有饱和性的酶可出现竞争性抑制
Content
I. Introduction
II.
III.
Materials and methods
Results
IV. Discussion
Abstract
Figure 1 Chemical structures of five PPIs.
AUCpo(PM)/AUCpo(EM), 7.4
Lansoprazole, omeprazole and pantoprazole are primarily metabolized by CYP2C19, an isoenzyme that exhibits genetic polymorphism AUCpo(PM)/AUCpo(EM),3.7