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E-raamat: Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism

Shufeng Zhou

Formaat: EPUB+DRM
Ilmumisaeg: 03-Sep-2018
Kirjastus: CRC Press Inc
Keel: eng
ISBN-13: 9781315360294

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Kirjastus: CRC Press Inc
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Cytochromes are proteins that catalyze electron transfer reactions of well-known metabolic pathways and are classified in various superfamilies. The CYP, or P450, superfamily accounts for 90% of the oxidative metabolism of clinical drugs. One member of this superfamily, P450 2D6 (or CYP2D6), singlehandedly metabolizes about 25% of all medications in the human liver. Cytochrome P450 2D6: Structure, Function, Regulation, and Polymorphism reviews the current knowledge of CYP2D6 as well as the maturing body of evidence indicating its significance to clinical and pharmacological researchers and practitioners.

This book focuses on the critical role CYP2D6 plays in the human liver. It examines the genetic, epigenetic, physiological, pathological, and structural factors of the gene that govern the highly variable metabolism of a number of drugs in clinical use. It highlights the impact of the functional roles of CYP2D6 on clinical practice and drug development and also discusses implications for precise medicine, strategies to avoid adverse drug reactions, and paths for future research.

Cytochrome P450 2D6 is a unique, valuable book focusing on a single but immensely powerful human gene. It provides the first single source of comprehensive information on CYP2D6 that serves as an important reference for medical, biomedical, pharmaceutical, and nursing researchers, practitioners, and students.

Preface

xiii

Author

Chapter 1 Introduction to Human Cytochrome P450 Superfamily

(100)

1.1 The Cytochrome P450s in Nature

(2)

1.2 Human CYP Superfamily

(19)

1.2.1 Members of the CYP Superfamily: Family, Subfamily, Clan, and Motif

(12)

1.2.2 Subcellular Location of CYPs

(1)

1.2.3 CYP-Mediated Metabolism of Xenobiotics and Endogenous Compounds

(1)

1.2.4 Structural Features of CYPs

(2)

1.2.5 Inhibition of CYPs

(1)

1.2.6 Regulation of CYPs via Nuclear Receptors, miRNAs, Inflammation, and Cytokines

(2)

1.2.7 Phenotypes and Polymorphisms of CYPs

(1)

1.2.8 CYP-Related Diseases

(1)

1.3 Human CYP1 Family

(4)

1.3.1 CYP1A1 (Aryl Hydrocarbon Hydroxylase)

(1)

1.3.2 CYP1A2 (Aryl Hydrocarbon Hydroxylase)

(1)

1.3.3 CYP1B1 (Aryl Hydrocarbon Hydroxylase)

(1)

1.4 Human CYP2ABFGST Cluster: CYP2A6, 2A7, 2A13, 2B6, 2F1, and 2S1

(6)

1.4.1 CYP2A6 (Coumarin 7-Hydroxylase)

(2)

1.4.2 CYP2A7

(1)

1.4.3 CYP2A13

(1)

1.4.4 CYP2B6

(2)

1.4.5 CYP2F1

(1)

1.4.6 CYP2S1

(1)

1.5 Human CYP2C Cluster: CYP2C8, 2C9, 2C18, and 2C19

(4)

1.5.1 CYP2C8

(1)

1.5.2 CYP2C9

(2)

1.5.3 CYP2C18 (S-Mephenytoin Hydroxylase)

(1)

1.5.4 CYP2C19

(1)

1.6 Other Human CYP2 Family Members

(4)

1.6.1 CYP2D6

(1)

1.6.2 CYP2E1

(1)

1.6.3 CYP2J2

(1)

1.6.4 CYP2R1

(1)

1.6.5 CYP2U1

(1)

1.6.6 CYP2W1

(1)

1.7 Human CYP3A Cluster: CYP3A4, 3A5, 3A7, and 3A43

(4)

1.7.1 CYP3A4

(3)

1.7.2 CYP3A5

(1)

1.7.3 CYP3A7

(1)

1.7.4 CYP3A43

(1)

1.8 Human CYP4ABXZ Cluster: CYP4A11, 4A22, 4B1, 4X1, and 4Z1

(1)

1.8.1 CYP4A11 (20-Hydroxyeicosatetraenoic Acid Synthase, Fatty Acid ω-Hydroxylase, and Lauric Acid ω-Hydroxylase)

(1)

1.8.2 CYP4A22 (Fatty Acid ω-Hydroxylase and Lauric Acid ω-Hydroxylase)

(1)

1.8.3 CYP4B1

(1)

1.9 Human CYP4F Cluster: CYP4F2, 4F3, 4F8, 4F11, 4F12, and 4F22

(2)

1.9.1 CYP4F2 (20-Hydroxyeicosatetraenoic Acid Synthase, Arachidonic Acid ω-Hydroxylase, and Leukotriene-B4 ω-Hydroxylase 1)

(1)

1.9.2 CYP4F3

(1)

1.9.3 CYP4F8

(1)

1.9.4 CYP4F11 (Phylloquinone ω-Hydroxylase and 3-Hydroxy Fatty Acid ω-Hydroxylase)

(1)

1.9.5 CYP4F12

(1)

1.9.6 CYP4F22

(1)

1.10 Other Human CYP4 Family Members

(1)

1.10.1 CYP4V2 (Docosahexaenoic Acid ω-Hydroxylase)

(1)

1.10.2 CYP4X1

(1)

1.10.3 CYP4Z1

(1)

1.11 Human CYP5 Family

(1)

1.11.1 CYP5A1 (Thromboxane A Synthase 1, TBXAS1)

(1)

1.12 Human CYP7 Family

(1)

1.12.1 CYP7A1 (Cholesterol 7α-Hydroxylase)

(1)

1.12.2 CYP7B1 (Oxysterol 7α-Hydroxylase 1)

(1)

1.13 Human CYP8 Family

(1)

1.13.1 CYP8A1 (Prostaglandin I2 Synthase, PGIS/PTGIS)

(1)

1.13.2 CYP8B1 (Sterol 12α-Hydroxylase)

(1)

1.14 Human CYP11 Family

(2)

1.14.1 CYP11A1 (Cholesterol Side-Chain Cleavage Enzyme)

(1)

1.14.2 CYP11B1 (Steroid 11β-Hydroxylase)

(1)

1.14.3 CYPI1B2 (Aldosterone Synthase/Steroid 11β/18-Hydroxylase)

(1)

1.15 Human CYP17 Family

(1)

1.15.1 CYP17A1 (Steroid 17α-Monooxygenase, 17α-Hydroxylase, 17,20 Lyase, and 17,20 Desmolase)

(1)

1.16 Human CYP19 Family

(1)

1.16.1 CYP19A1 (Aromatase)

(1)

1.17 Human CYP20 Family

(1)

1.17.1 CYP20A1

(1)

1.18 Human CYP21 Family

(1)

1.18.1 CYP21A2 (Steroid 21-Hydroxylase)

(1)

1.19 Human CYP24 Family

(1)

1.19.1 CYP24A1 (1,25-Dihydroxyvitamin D3 24-Hydroxylase, Vitamin D 24-Hydroxylase/ Vitamin D3 24-Hydroxylase)

(1)

1.20 Human CYP26 Family

(2)

1.20.1 CYP26A1 (Retinoic Acid 4-Hydroxylase)

(1)

1.20.2 CYP26B1

(1)

1.20.3 CYP26C1

(1)

1.21 Human CYP27 Family

(2)

1.21.1 CYP27A1 (Sterol 27-Hydroxylase)

(1)

1.21.2 CYP27B1 (Mitochondria) 25-Hydroxyvitamin D 1α-Hydroxylase)

(1)

1.21.3 CYP27C1

(1)

1.22 Human CYP39A1, 46A1, and 51A1

(1)

1.22.1 CYP39A1 (Oxysterol 7α-Hydroxylase 2)

(1)

1.23 Human CYP46 Family

(1)

1.23.1 CYP46A1 (Cholesterol 24-Hydroxylase)

(1)

1.24 Human CYP51 Family

(1)

1.24.1 CYP51A1 (Lanosterol 14α-Demethylase/Sterol 14α-Demethylase)

(1)

1.25 Highlights of This Book

(1)

References

(41)

Chapter 2 Mammalian CYP2D Members: A Comparison of Structure, Function, and Regulation

101

(38)

2.1 Introduction

101

(1)

2.2 Rat Cyp2d Subfamily: Cyp2d1, 2d2, 2d3, 2d4, and 2d5

102

(17)

2.2.1 Tissue Distribution of Rat Cyp2ds

102

(10)

2.2.2 Substrates of Rat Cyp2ds

112

(1)

2.2.3 Differences in Rat Cyp2d-Dependent Metabolism

113

(1)

2.2.4 Dark Agouti Rats as a Cyp2d2-Deficient Model

114

(3)

2.2.5 Regulation of Rat Cyp2ds

117

(1)

2.2.6 Inhibitors of Rat CYP2ds and Cyp2d-Mediated Drug-Drug Interactions

118

(1)

2.3 Mouse Cyp2d Subfamily: Cyp2d9-2d13, 2d22, 2d26, 2d34, and 2d40

119

(2)

2.3.1 Tissue Distribution of Mouse Cyp2ds

119

(1)

2.3.2 Substrate Specificity of Mouse Cyp2ds

120

(1)

2.3.3 Cyp2d Knockout and CYP2D6 Transgenic Mouse Model

120

(1)

2.4 Bovine CYP2D14

121

(1)

2.5 Dog CYP2D15

121

(4)

2.5.1 Cloning and Purification of Dog CYP2D15

122

(1)

2.5.2 Tissue Distribution of Dog CYP2D15

122

(1)

2.5.3 Substrate Specificity of Dog CYP2D15

122

(2)

2.5.4 Induction of Dog CYP2D15

124

(1)

2.5.5 Inhibitors of Dog CYP2D15

125

(1)

2.6 Guinea Pig Cyp2d16

125

(1)

2.6.1 Tissue Distribution of Guinea Pig Cyp2d16

125

(1)

2.6.2 Substrate Specificity of Guinea Pig Cyp2d16

125

(1)

2.6.3 Regulation of Guinea Pig Cyp2d16

125

(1)

2.7 Macaque CYP2D17, 2D29, 2D42, and 2D44

126

(1)

2.7.1 Cynomolgus Monkey CYP2D17 and 2D44

126

(1)

2.7.2 Japanese Monkey CYP2D29

127

(1)

2.8 Marmoset CYP2D8, 2DI9, and 2D30

127

(1)

2.9 Rabbit CYP2D23 and CYP2D24

128

(1)

2.10 Pig CYP2D25

128

(1)

2.10.1 Cloning and Purification of Pig CYP2D25

128

(1)

2.10.2 Catalytic Activity of Pig CYP2D25

128

(1)

2.11 Syrian Hamster Cyp2d27

129

(1)

2.12 Chicken CYP2D49

129

(1)

2.13 Horse CYP2D50

129

(1)

2.14 Conclusions and Future Perspectives

130

(1)

References

130

(9)

Chapter 3 Substrates of Human CYP2D6

139

(150)

3.1 Introduction

139

(1)

3.2 Probes of CYP2D6

139

(2)

3.2.1 Sparteine and Debrisoquine

139

(1)

3.2.2 Dextromethorphan

140

(1)

3.2.3 Bufuralol and Tramadol

140

(1)

3.3 Therapeutic Drugs as Substrates of CYP2D6

141

(91)

3.3.1 Drugs Acting on the Central Nervous System

141

(36)

3.3.1.1 Tricyclic Antidepressants

141

(5)

3.3.1.2 Selective Serotonin Reuptake Inhibitors

146

(5)

3.3.1.3 Other Antidepressants

151

(2)

3.3.1.4 Antipsychotics

153

(9)

3.3.1.5 Hypnotics

162

(1)

3.3.1.6 Opioids and Opioid Receptor Antagonists

162

(3)

3.3.1.7 Antiemetics

165

(4)

3.3.1.8 Antimigraine Drugs

169

(1)

3.3.1.9 Antiparkinsonism Agents

170

(1)

3.3.1.10 Centrally Acting Cholinesterase Inhibitors

171

(4)

3.3.1.11 Drugs for Senile Dementia

175

(1)

3.3.1.12 Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder

175

(1)

3.3.1.13 Nonnarcotic Analgesics

175

(1)

3.3.1.14 Drugs for Huntington's Disease Chorea

176

(1)

3.3.2 Cardiovascular Drugs

177

(25)

3.3.2.1 Antianginal Drugs

177

(3)

3.3.2.2 Antiarrhythmics

180

(10)

3.3.2.3 Antiplatelet Agents

190

(3)

3.3.2.4 β-Blockers

193

(5)

3.3.2.5 Calcium Channel Blockers

198

(4)

3.3.3 Antihistamines

202

(6)

3.3.3.1 Azelastine

203

(1)

3.3.3.2 Chlorpheniramine

203

(1)

3.3.3.3 Cinnarizine and Flunarizine

203

(1)

3.3.3.4 Diphenhydramine

204

(1)

3.3.3.5 Loratadine

204

(1)

3.3.3.6 Mequitazine

205

(1)

3.3.3.7 Oxatomide

205

(2)

3.3.3.8 Terfenadine

207

(1)

3.3.4 Anti-HIV Agents

208

(7)

3.3.4.1 HIV Protease Inhibitors

208

(2)

3.3.4.2 Nonnucleoside Reverse Transcriptase Inhibitors

210

(5)

3.3.5 Antimalarial Drugs

215

(2)

3.3.5.1 Amodiaquine

215

(1)

3.3.5.2 Chloroquine

215

(1)

3.3.5.3 Halofantrine

215

(2)

3.3.5.4 Phenoxypropoxybiguanides

217

(1)

3.3.6 Hypolipidemic Agents

217

(1)

3.3.6.1 Fluvastatin

217

(1)

3.3.6.2 Pactimibe

218

(1)

3.3.7 Muscarinic Receptor Antagonists

218

(1)

3.3.7.1 Tolterodine

218

(1)

3.3.8 Nonsteroidal Anti-Inflammatory Drugs

218

(2)

3.3.8.1 Acetaminophen

218

(2)

3.3.8.2 Indomethacin

220

(1)

3.3.9 Oral Hypoglycemic Drugs

220

(1)

3.3.9.1 Phenformin

220

(1)

3.3.10 Selective Estrogen Receptor Modulators

221

(6)

3.3.10.1 Tamoxifen

222

(4)

3.3.10.2 Droloxifene

226

(1)

3.3.10.3 Enclomifene

226

(1)

3.3.10.4 Lasofoxifene

226

(1)

3.3.11 Selective Phosphodiesterase Type 5 Inhibitors

227

(1)

3.3.12 Other Drugs and Compounds

227

(5)

3.4 Drugs of Abuse as Substrates of CYP2D6

232

(4)

3.4.1 Amphetamine Derivatives

232

(1)

3.4.2 β-Carbolines

232

(1)

3.4.3 Designer Drugs

233

(1)

3.4.4 Indolealkylamines

234

(2)

3.5 Fluorescent Probes as Substrates of CYP2D6

236

(1)

3.6 Plant Alkaloids, Toxicants, and Environmental Compounds as Substrates of CYP2D6

237

(3)

3.6.1 Plant Alkaloids

237

(1)

3.6.2 Neurotoxin

237

(1)

3.6.3 Herbicides and Pesticides

238

(2)

3.7 Endogenous Compounds as Substrates of CYP2D6

240

(5)

3.7.1 5-Methoxyindolethylamine

240

(1)

3.7.2 Tyramines

240

(1)

3.7.3 Steroids and Neurosteroids

241

(3)

3.7.4 Endogenous Morphine

244

(1)

3.7.5 Endocannabinoid Arachidonoylethanolamide (Anandamide)

244

(1)

3.8 Structure-Activity Relationships of CYP2D6 Substrates

245

(1)

3.9 Conclusions and Future Directions

246

(10)

References

256

(33)

Chapter 4 Inhibitors of Human CYP2D6

289

(26)

4.1 Introduction

289

(1)

4.2 Selective Inhibitors of CYP2D6

289

(10)

4.3 Mechanism-Based Inhibitors of CYP2D6

299

(1)

4.3.1 Paroxetine

299

(1)

4.3.2 Cimetidine

299

(1)

4.3.3 Metoclopramide

299

(1)

4.3.4 Pimozide

300

(1)

4.3.5 Other Compounds

300

(1)

4.4 Reversible and Mixed-Type Inhibitors of CYP2D6

300

(7)

4.4.1 Central Nervous System Drugs

300

(3)

4.4.1.1 Antipsychotics

300

(1)

4.4.1.2 SSRIs

301

(1)

4.4.1.3 Tricyclic Antidepressants

302

(1)

4.4.1.4 Other Antidepressants

302

(1)

4.4.1.5 Narcotics

302

(1)

4.4.1.6 Other Central Nervous System Drugs

302

(1)

4.4.2 H1 Receptor Antagonists

303

(1)

4.4.3 Antifungal Agents

304

(1)

4.4.4 Anti-HIV Agents

304

(1)

4.4.5 Steroids

304

(1)

4.4.6 Other Drugs

304

(2)

4.4.7 Amphetamine Analogs

306

(1)

4.4.8 Natural and Herbal Compounds

307

(1)

4.5 Structure-Activity Relationships of CYP2D6 Inhibitors

307

(1)

4.6 Conclusions and Future Directions

308

(1)

References

308

(7)

Chapter 5 Regulation of Human CYP2D6

315

(26)

5.1 Introduction

315

(1)

5.2 Effects of Physiological Factors on CYP2D6 Activity

316

(2)

5.2.1 Gender

316

(1)

5.2.2 Developmental Changes (Ontogeny) of CYP2D6 Expression and Activity

316

(1)

5.2.3 Pregnancy Induces CYP2D6

317

(1)

5.2.4 Fasting

318

(1)

5.3 Effects of Environmental Factors on CYP2D6 Activity

318

(2)

5.3.1 Smoking

318

(1)

5.3.2 Alcoholic Cirrhosis

319

(1)

5.3.3 Herbal Medicines

319

(1)

5.4 Human CYP2D6 Is Largely Uninducible by Prototypical Inducers of CYPs

320

(1)

5.4.1 In Vitro Studies

320

(1)

5.4.2 In Vivo Studies

320

(1)

5.5 Transcriptional and Posttranscriptional Regulation of CYP2D6 by HNF-4α and FXR

321

(2)

5.5.1 Transcriptional Regulation of CYP2D6 by HNF-4α

321

(1)

5.5.2 Transcriptional Regulation of CYP2D6 by FXR

322

(1)

5.6 Posttranslational Regulation of CYP2D6

323

(1)

5.7 Genome-Wide Association Studies on the Regulation of CYP2D6

323

(1)

5.8 Effects of Diseases on CYP2D6 Expression and Activity

324

(3)

5.8.1 Liver Diseases

324

(2)

5.8.2 Chronic Renal Failure

326

(1)

5.8.3 Diabetes

326

(1)

5.8.4 Rheumatoid Arthritis

327

(1)

5.8.5 Cytokines and Inflammation

327

(1)

5.9 Conclusions and Future Directions

327

(1)

References

327

(14)

Chapter 6 Structure and Function of Human CYP2D6

341

(74)

6.1 Introduction

341

(1)

6.2 Pharmacophore Models and Structural Requirements of CYP2D6 Ligands

341

(2)

6.3 Homology Modeling Studies of Human CYP2D6

343

(3)

6.3.1 Homology Models Derived from Bacterial CYPs

343

(1)

6.3.2 Homology Models Derived from Rabbit CYP2C5 Structures

344

(2)

6.4 Site-Directed Mutagenesis Studies of CYP2D6

346

(12)

6.4.1 Pro34

346

(1)

6.4.2 Gly42

346

(1)

6.4.3 Ala90

347

(1)

6.4.4 Asp100

347

(1)

6.4.5 Thr107

347

(1)

6.4.6 Phe120, Phe481, and Phe483

348

(1)

6.4.7 Trp128

349

(1)

6.4.8 Val136

350

(1)

6.4.9 Glu156

350

(1)

6.4.10 Gly169

350

(1)

6.4.11 Glu216 and Asp301

350

(3)

6.4.12 Lys281

353

(1)

6.4.13 Glu222

353

(1)

6.4.14 Arg296

353

(1)

6.4.15 Ser304

353

(1)

6.4.16 Thr309 and Thr312

354

(1)

6.4.17 His324

355

(1)

6.4.18 Val338

356

(1)

6.4.19 Met374

356

(1)

6.4.20 Glu410

356

(1)

6.4.21 Arg440

356

(1)

6.4.22 Ser486

356

(2)

6.5 Studies Using Aryldiazene Probes

358

(1)

6.6 Antibody Studies of Human CYP2D6

359

(1)

6.7 Other Molecular Modeling Studies

360

(1)

6.8 X-Ray Crystallographic Study of Human CYP2D6 and Functional Implications

360

(7)

6.8.1 Secondary Structure of CYP2D6 in Comparison with CYP2C9

360

(1)

6.8.2 Active-Site Cavity of CYP2D6

361

(1)

6.8.3 Key Active-Site Amino Acids of CYP2D6

362

(2)

6.8.3.1 Ile106

362

(1)

6.8.3.2 Leu213 and Val308

362

(1)

6.8.3.3 Glu216

362

(1)

6.8.3.4 Asp301

362

(1)

6.8.3.5 Thr309

363

(1)

6.8.3.6 Met374

363

(1)

6.8.3.7 Phe120, Phe481, and Phe483

364

(1)

6.8.3.8 Arg441

364

(1)

6.8.4 Heme-Binding Site

364

(1)

6.8.5 Access and Egress Channels

364

(1)

6.8.6 Binding Region for Cytochrome P450 Reductase

365

(1)

6.8.7 Plasticity of CYP2D6

365

(1)

6.8.8 A Comparison of the Homology Model and Crystal Structure of CYP2D6

366

(1)

6.8.9 Binding of Atypical Substrates to Human CYP2D6

366

(1)

6.9 Bindings Modes of the Substrates and Inhibitors with CYP2D6

367

(40)

6.9.1 Binding Modes of the Substrates with CYP2D6 Active Site

368

(7)

6.9.2 Binding Modes of the Inhibitor with the CYP2D6 Active Site

375

(32)

6.10 Conclusions and Future Directions

407

(1)

References

407

(8)

Chapter 7 Clinical Pharamcogenomics of Human CYP2D6

415

(68)

7.1 Introduction

415

(1)

7.2 Interindividual Variability in CYP2D6 Expression and Activity

416

(1)

7.3 Alleles of the CYP2D6 Gene

416

(14)

7.3.1 Null Alleles of CYP2D6

416

(11)

7.3.1.1 Null Alleles Attributed to Single Base Mutation or Small Insertions/Deletions

425

(1)

7.3.1.2 Nonfunctional Full-Length Coded Alleles

426

(1)

7.3.1.3 Deletion of the Entire Gene

426

(1)

7.3.1.4 Formation of Hybrid Genes

426

(1)

7.3.2 Alleles with Partial or Residual Function

427

(2)

7.3.3 Alleles with Largely Normal or Increased Activity

429

(1)

7.3.4 Duplication and Multiduplication of CYP2D6

429

(1)

7.4 Ethnic Variation in the Distribution of CYP2D6 Polymorphisms

430

(1)

7.5 Antianginal Drugs

431

(1)

7.5.1 Perhexiline

431

(1)

7.6 Antiarrhythmic Drugs

431

(5)

7.6.1 Flecainide

432

(1)

7.6.2 Mexiletine

433

(1)

7.6.3 Propafenone

434

(1)

7.6.4 Vernakalant

435

(1)

7.7 Antidepressants

436

(7)

7.7.1 Tricyclic Antidepressants

436

(3)

7.7.1.1 Amitriptyline and Nortriptyline

436

(1)

7.7.1.2 Clomipramine

436

(1)

7.7.1.3 Doxepin

437

(1)

7.7.1.4 Imipramine and Desipramine

437

(1)

7.7.1.5 Maprotiline

438

(1)

7.7.1.6 Trimipramine

438

(1)

7.7.2 Selective Serotonin Reuptake Inhibitors

439

(3)

7.7.2.1 Citalopram

439

(1)

7.7.2.2 Fluvoxamine

439

(1)

7.7.2.3 Fluoxetine

440

(1)

7.7.2.4 Paroxetine

441

(1)

7.7.2.5 Sertraline

441

(1)

7.7.3 Other Antidepressants

442

(1)

7.7.3.1 Mianserin

442

(1)

7.7.3.2 Mirtazapine

442

(1)

7.7.3.3 Venlafaxine

442

(1)

7.7.3.4 Miscellaneous Antidepressants

443

(1)

7.8 Antipsychotics

443

(6)

7.8.1 Aripiprazole

443

(1)

7.8.2 Chlorpromazine

444

(1)

7.8.3 Haloperidol

444

(2)

7.8.4 Perphenazine

446

(1)

7.8.5 Risperidone

446

(1)

7.8.6 Thioridazine

447

(1)

7.8.7 Zuclopenthixol

447

(1)

7.8.8 Miscellaneous and Atypical Antipsychotics

448

(1)

7.8.8.1 Clozapine

448

(1)

7.8.8.2 Olanzapine

448

(1)

7.8.8.3 Miscellaneous Antipsychotics

448

(1)

7.9 Centrally Acting Cholinesterase Inhibitors

449

(1)

7.9.1 Donepezil

449

(1)

7.9.2 Galantamine

449

(1)

7.10 Drugs for the Treatment of Attention-Deficit/Hyperactivity Disorder

449

(2)

7.10.1 Atomoxetine

449

(2)

7.11 Drugs for the Treatment of Senile Dementia

451

(1)

7.11.1 Nicergoline

451

(1)

7.12 Antimuscarinic Drugs

451

(1)

7.12.1 Tolterodine

451

(1)

7.13 Antiemetics

451

(1)

7.13.1 Dolasetron

451

(1)

7.13.2 Ondansetron

451

(1)

7.13.3 Tropisetron

451

(1)

7.14 Antihistamine

452

(1)

7.14.1 Chlorpheniramine

452

(1)

7.14.2 Diphenhydramine

452

(1)

7.14.3 Loratadine

452

(1)

7.15 β-Blockers

452

(2)

7.15.1 Carvedilol

452

(1)

7.15.2 Metoprolol

453

(1)

7.15.3 Propranolol

454

(1)

7.15.4 Timolol

454

(1)

7.16 Opioids

454

(4)

7.16.1 Codeine

455

(1)

7.16.2 Dihydrocodeine

455

(1)

7.16.3 Hydrocodone

455

(1)

7.16.4 Oxycodone

456

(1)

7.16.5 Methadone

456

(1)

7.16.6 Tramadol

457

(1)

7.17 Oral Hypoglycemic Drugs

458

(1)

7.17.1 Phenformin

458

(1)

7.18 Selective Estrogen Receptor Modulators

459

(1)

7.18.1 Tamoxifen

459

(1)

7.19 Other Drugs

460

(1)

7.19.1 Cevimeline

460

(1)

7.19.2 Darifenacin

460

(1)

7.19.3 Tetrabenazine

460

(1)

7.19.4 Vortioxetine

460

(1)

7.20 Conclusions and Future Perspectives

460

(3)

References

463

(20)

Chapter 8 General Discussion about Human CYP2D6

483

(12)

References

489

(6)

Index

495

Shufeng Zhou is the associate vice president of Global Medical Development and associate dean of international research in the College of Pharmacy of the University of South Florida in Tampa. He earned his PhD in pharmacology from the University of Auckland in New Zealand. His major research interests are systems pharmacology, drug metabolism and drug transport, pharmacokinetics/pharmacometrics, pharmacogenomics, nanomedicine, and Chinese medicine. He has published more than 450 peer-reviewed papers, 20 books and book chapters, and more than 440 conference abstracts. He was one of the Highly Cited Researchers of 2014 according to Thomson Reuter and has given more than 150 invited seminars and keynote presentations to academic institutions, government agencies, and high-profile international conferences. He serves as an editor or the editor in chief of at least 21 biomedical journals and is an editorial board member of more than 75 medical and pharmacological journals. He has received several national and international awards, is a voting member of US Pharmacopeia, a consultant for the World Health Organization and the Food and Drug Administration, and a council member or chair of several national and international professional societies.

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