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Metabolism of Drugs and Other Xenobiotics

ISBN: 978-3-527-32903-8
753 pages
May 2012
Metabolism of Drugs and Other Xenobiotics (352732903X) cover image
A practice-oriented desktop reference for medical professionals, toxicologists and pharmaceutical researchers, this handbook provides
systematic coverage of the metabolic pathways of all major classes of xenobiotics in the human body. The first part comprehensively reviews
the main enzyme systems involved in biotransformation and how they are orchestrated in the body, while parts two to four cover the three
main classes of xenobiotics: drugs, natural products, environmental pollutants. The part on drugs includes more than 300 substances from
five major therapeutic groups (central nervous system, cardiovascular system, cancer, infection, and pain) as well as most drugs of abuse

including nicotine, alcohol and "designer" drugs. Selected, well-documented case studies from the most important xenobiotics classes illustrate general principles of metabolism, making this equally useful for teaching courses on pharmacology, drug metabolism or molecular
toxicology.
Of particular interest, and unique to this volume is the inclusion of a wide range of additional xenobiotic compounds, including food supplements, herbal preparations, and agrochemicals.
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Part One Biochemistry and Molecular Genetics of Drug Metabolism 1

1 Drug-Metabolizing Enzymes – An Overview 3
Pavel Anzenbacher and Eva Anzenbacherová

1.1 Introduction: Fate of a Drug in the Human Body 3

1.2 Classifi cation Systems of Drug-Metabolizing Enzymes According to Different Criteria 4

1.3 Overview of the Most Important Drug-Metabolizing Enzymes 6

Acknowledgments 20

References 20

2 Cytochromes P450 27
F. Peter Guengerich

2.1 Introduction and Historical Perspective 27

2.2 Nomenclature and Gene Organization 29

2.3 Regulation 32

2.4 Polymorphisms 35

2.5 Protein Structure 37

2.6 Catalytic Mechanisms 40

2.7 What Determines P450 Catalytic Selectivity? 45

2.8 Oxidative Stress and P450s 47

2.9 Relevance in Drug Metabolism and Clinical Medicine 48

References 53

3 UDP-Glucuronosyltransferases 67
Christian P. Strassburg and Sandra Kalthoff

3.1 Introduction 67

3.2 A Simple Phenotype: Unconjugated Nonhemolytic Hyperbilirubinemia and Glucuronidation 67

3.3 Organization of UGTs and the UGT1A Gene Locus 68

3.4 UGT1A Gene Nomenclature 70

3.5 Human UGT1A Gene Locus and Sequence Variability 71

3.6 Glucuronidation of Bilirubin 78

3.7 UGT1A1 Gene 79

3.8 Is There an Advantage or Risk Associated with UGT1A1 Variability? 80

3.9 UGT1A1 Gene and Pharmacogenetic Protection 82

3.10 UGT1A1 Gene and Pharmacogenetic Risks 83

3.11 UGT1A1 Variability and Cancer Risk 86

3.12 UGT1A3 Gene 87

3.13 UGT1A7 Gene 88

3.14 Transcriptional Regulation of UGT1A Genes 95

3.15 Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Regulation of UGT1A Genes 95

3.16 Regulation by Hepatic Nuclear Factors 97

3.17 Regulation by the Farnesoid X Receptor 97

3.18 Regulation by Nuclear Factor Erythroid 2-Related Factor 2 98

3.19 Regulation by Splice Variants 98

3.20 Animal Models to Study UGT1A Genes 99

3.21 Outlook 100

Acknowledgments 101

References 101

4 Sulfotransferases 117
Michael W. H. Coughtrie

4.1 Introduction 117

4.2 Background 118

4.3 PAPS Synthesis 119

4.4 SULT Enzyme Family 121

4.5 Assays for SULT Activity 128

4.6 Structure and Function of SULT 128

4.7 SULT Pharmacogenetics 132

4.8 Bioactivation and the Role of SULTs in Toxicology 133

4.9 Conclusions and Future Perspectives 135

References 135

5 Glutathione S-Transferases 147
Miroslav Dostalek and Anna-Katarina Stark

5.1 Introduction and History 147

5.2 Nomenclature, Structure, and Function 148

5.3 Substrates 151

5.4 Regulation, Induction, and Inhibition 151

5.5 Gene Polymorphism of GSTs 155

References 1576

Hydrolytic Enzymes 165
Bingfang Yan

6.1 Carboxylesterases 165

6.2 Epoxide Hydrolases 178

6.3 Paraoxonases 183

6.4 Other Hydrolases 188

References 191

7 Transporting Systems 199
Anne T. Nies, Claudia Resch, and Tadashi Namisaki

7.1 Introduction 199

7.2 Classification of Drug Transporters and Transport Mechanisms 199

7.3 Drug Transporters of the SLC Superfamily 200

7.4 ABC Drug Transporters 208

7.5 Drug Transporters and Disease 208

7.6 Drug Transporters and Pharmacokinetics 212

7.7 Role of Drug Transporters in Chemotherapy Resistance 214

7.8 Pharmacogenomics of Drug Transporters: Implications for Clinical Drug Response 215

Acknowledgments 215

References 216

8 Transcriptional Regulation of Human Drug-Metabolizing Cytochrome P450 Enzymes 223
Zdenek Dvorak

8.1 Factors Affecting Drug-Metabolizing Cytochromes P450 223

8.2 Transcriptional Regulation of CYP 224

8.3 Regulation of Drug-Metabolizing CYPs 230

Acknowledgments 238

References 238

9 Importance of Pharmacogenomics 259
Ulrich M. Zanger, Kathrin Klein, and Jessica Rieger

9.1 Introduction 259

9.2 Pharmacogenetic Polymorphisms 260

9.3 Polygenic and Multifactorial Aspects of Drug Metabolism Phenotype 270

9.4 Genomics Technologies and Approaches 273

9.5 Conclusions 276

References 276

Part Two Metabolism of Drugs 285

10 Introduction to Drug Metabolism 287
Ulrich M. Zanger

10.1 Introduction 287

10.2 Historical Aspects 287

10.3 Diversity of Drug Metabolic Pathways 288

10.4 Infl uence of Drug Metabolism on Pharmacological Activity 289

10.5 Biotoxification 290

10.6 Extrahepatic Drug Metabolism 290

10.7 Factors Affecting Drug Metabolism Activity 291

10.8 Conclusions 296

References 296

11 Central Nervous System Drugs 301
Pierre Baumann and Christoph Hiemke

11.1 Introduction 301

11.2 Antidepressants 301

11.3 Antipsychotics 306

11.4 Tranquillizers and Hypnotic Agents 309

11.5 Psychostimulants 311

11.6 Anticonvulsants and Mood Stabilizers 311

11.7 Agents for Dementia and Cognitive Enhancers 313

11.8 Antimigraine Drugs 313

11.9 Other Drugs 314

11.10 Conclusions 314

References 315

12 Cardiovascular Drugs 331
Stephan Riedmaier and Ulrich M. Zanger

12.1 Introduction 331

12.2 RAAS as a Target for Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor Blockers 331

12.3 Adrenergic Receptor Agonists 337

12.4 Adrenergic Receptor Antagonists 339

12.5 Diuretics 342

12.6 Antiarrhythmics 349

12.7 Anticoagulants 351

12.8 Cholesterol-Lowering Drugs 353

References 357

13 Anticancer Drugs 365
Matthias Schwab, Elke Schaeffeler, and Hiltrud Brauch

13.1 Introduction 365

13.2 Alkylating Drugs 365

13.3 Platinum-Containing Agents 367

13.4 Antimetabolites 367

13.5 Natural Products 370

13.6 Endocrine Therapy 372

13.7 Histone Deacetylase Inhibitor (Vorinostat) 373

13.8 Tyrosine Kinase Inhibitors 373

13.9 Proteasome Inhibitor (Bortezomib) 374

References 374

14 Antimicrobial Agents 379
Chantal Csajka, Oscar Marchetti, Oriol Manuel, Laurent Decosterd, and Amalio Telenti

14.1 Introduction 379

14.2 Pharmacokinetics/Pharmacodynamics of the Main Families of Antimicrobial Agents 380

14.3 Pharmacogenetics 393

14.4 Conclusions 397

Acknowledgments 398

References 398

15 Drugs against Acute and Chronic Pain 403
Andrew A. Somogyi and Janet K. Coller

15.1 Introduction 403

15.2 Acute Pain 403

15.3 Chronic Pain 410

References 421

16 Drugs of Abuse (Including Designer Drugs) 429
Markus R. Meyer and Hans H. Maurer

16.1 Introduction 429

16.2 Classic Drugs of Abuse 432

16.3 Designer Drugs of Abuse 435

References 450

17 Nicotine Metabolism and its Implications 465
Andy Z.X. Zhu and Rachel F. Tyndale

17.1 Introduction 465

17.2 Absorption and Distribution of Nicotine 465

17.3 Excretion of Nicotine 466

17.4 Metabolism of Nicotine 468

17.5 Sources of Variation in Nicotine Metabolism 471

17.6 Implications of Variation in Nicotine Metabolism and CYP2A6 Activity 481

17.7 Conclusions 483

Acknowledgments 483

References 484

18 Metabolism of Alcohol and its Consequences 493
Helmut K. Seitz and Sebastian Mueller

18.1 Introduction 493

18.2 Properties and Sources of Ethanol 494

18.3 Ethanol Absorption and Elimination 495

18.4 Ethanol Metabolism 497

Acknowledgments 511

References 511

Part Three Metabolism of Natural Compounds 517

19 Introduction and Overview 519
Michael Murray

19.1 Introduction 519

19.2 Terpenoids: A Structurally Complex Group of Natural Products 522

19.3 Other Classes of Natural Products 531

19.4 Summary and Conclusions 536

Acknowledgments 536

References 536

20 Flavonoids 543
Petr Hodek

20.1 Flavonoids – Plant Phytochemicals 543

20.2 Absorption and Metabolism of Flavonoids 545

20.3 Interactions of Flavonoids with Mammalian Proteins with Possible Implications for Drug Metabolism 554

20.4 Dietary Flavonoids – Health Issues 562

20.5 Flavonoid–Drug Interactions 570

20.6 Conclusion – Double-Edged Sword Properties of Flavonoids 573

References 574

21 St John’s Wort (Hypericum perforatum L.) 583
Miroslav Dostalek and Anna-Katarina Stark

21.1 The Name Hypericum 583

21.2 Chemical Constituents of Hypericum perforatum 583

21.3 Clinical Pharmacology of H. perforatum 587

21.4 Pharmacokinetics and Pharmacokinetic Interactions of H. perforatum 588

21.5 In Vitro Studies 591

21.6 In Vivo Studies 592

Acknowledgments 592

References 603

22 Food Components and Supplements 611
Alexandr Parlesak

22.1 Introduction 611

22.2 Food Contaminants 612

22.3 Vitamins 616

22.4 Macronutrients 620

22.5 Secondary Plant Metabolites 622

22.6 Probiotics and Prebiotics in the Modulation of Drug Metabolism 628

References 629

Part Four Metabolism of Unnatural Xenobiotics 637

23 Environmental Pollutants 639
Marie Stiborova

23.1 Introduction – An Overview 639

23.2 Overview of Environmental Pollutants 641

23.3 Toxic and Hazardous Environmental Pollutants Interacting with Drug Metabolism 642

23.4 Summary 660

References 661

24 Environmental Estrogens 671
Miroslav Machala and Jan Vondrácˇek

24.1 Introduction 671

24.2 Estrogen Receptor Signaling Pathways 672

24.3 Agonistic/Antagonistic Effects of Xenobiotics on ERs 673

24.4 Effects of EDCs on Biosynthesis and Metabolism of Estrogens 676

24.5 Case of Polychlorinated Biphenyls 677

24.6 Conclusions 678

References 679

25 Biotransformation of Insecticides 685
Corie A. Ellison, Alice L. Crane, and James R. Olson

25.1 Introduction to Insecticides 685

25.2 Metabolism of Insecticides 688

25.3 Extrahepatic Metabolism of Insecticides 693

25.4 Factors Affecting Metabolism 694

25.5 Conclusions 697

Note 697

References 697

Index 703

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Pavel Anzenbacher heads the Department of Pharmacology at Palacky University, Olomouc (Czech Republic) and is vicepresident of the Czech Society of Clinical and Experimental Pharmacology and Toxicology. Having obtained his academic degrees from Charles University, Prague and from the Academy of Sciences of the Czech Republic he joined the Faculty of Medicine at Palacky University. His scientific contacts and stays have included e.g. the Princeton University, Vanderbilt University, Nashville, University of Connecticut, INSERM Montpellier, University of Lubeck, Technical University Berlin and Jagellonian University Cracow. Professor Anzenbacher has authored over 150 original scientific publications and has, among other honours, received the Fogarty Award of the USPHS.

Ulrich M. Zanger is deputy head of the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart (Germany). A chemist by training, he began to work on drug metabolism at the Biocenter of the University of Basel, Switzerland, where he obtained a PhD
degree in biochemistry. He undertook postdoctoral studies at the Southwestern Medical Center at Dallas, Texas, before returning to Basel and later moving to Stuttgart. His major research interests are in human drug metabolizing cytochromes P450 and in basic and clinical aspects
of pharmacogenetics/genomics. Professor Zanger has authored more than 130 scientific articles and is lecturing in pharmacology and toxicology at the University of Tübingen.
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“Overall therefore, a book which can be read in its own right for the first half and then a valuable source of reference for the second half.  A useful tome to have on the bookshelf for anyone in the field.”  (British Toxicology Society, 1 July 2013)

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