Table of Contents

Part One Biochemistry and Molecular Genetics of Drug Metabolism 1 1 Drug-Metabolizing Enzymes - An Overview 3 Pavel Anzenbacher and Eva Anzenbacherova 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 Vondrac ek 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

About the Author

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 Tubingen.

Reviews

"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)