Metabolism of Drugs and Other Xenobiotics

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)

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.

Preface PART ONE: Biochemistry and Molecular Genetics of Drug Metabolism DRUG-METABOLIZING ENZYMES - AN OVERVIEW Introduction: Fate of a Drug in the Human Body Classification Systems of Drug-Metabolizing Enzymes According to Different Criteria Overview of the Most Important Drug-Metabolizing Enzyme CYTOCHROMES P450 Introduction and Historical Perspective Nomenclature and Gene Organization Regulation Polymorphisms Protein Structure Catalytic Mechanisms What Determines P450 Catalytic Selectivity? Oxidative Stress and P450s Relevance in Drug Metabolism and Clinical Medicine UDP-GLUCURONOSYLTRANSFERASES Introduction A Simple Phenotype: Unconjugated Nonhemolytic Hyperbilirubinemia and Glucuronidation Organization of UGTs and the UGT1A Gene Locus UGT1A Gene Nomenclature Human UGT1A Gene Locus and Sequence Variability Glucuronidation of Bilirubin UGT1A1 Gene Is There an Advantage or Risk Associated with UGT1A1 Variability? UGT1A1 Gene and Pharmacogenetic Protection UGT1A1 Gene and Pharmacogenetic Risks UGT1A1 Variability and Cancer Risk UGT1A3 Gene UGT1A7 Gene Transcriptional Regulation of UGT1A Genes Aryl Hydrocarbon Receptor/Aryl Hydrocarbon Receptor Nuclear Translocator Regulation of UGT1A Genes Regulation by Hepatic Nuclear Factors Regulation by the Farnesoid X Receptor Regulation by Nuclear Factor Erythroid 2-Related Factor 2 Regulation by Splice Variants Animal Models to Study UGT1A Genes Outlook SULFOTRANSFERASES Introduction Background PAPS Synthesis SULT Enzyme Family Assays for SULT Activity Structure and Function of SULT SULT Pharmacogenetics Bioactivation and the Role of SULTs in Toxicology Conclusions and Future Perspectives GLUTATHIONE S-TRANSFERASES Introduction and History Nomenclature, Structure, and Function Substrates Regulation, Induction, and Inhibition Gene Polymorphism of GSTs HYDROLYTIC ENZYMES Carboxylesterases Epoxide Hydrolases Paraoxonases Other Hydrolases TRANSPORTING SYSTEMS Introduction Classification of Drug Transporters and Transport Mechanisms Drug Transporters of the SLC Superfamily ABC Drug Transporters Drug Transporters and Disease Drug Transporters and Pharmacokinetics Role of Drug Transporters in Chemotherapy Resistance Pharmacogenomics of Drug Transporters: Implications for Clinical Drug Response TRANSCRIPTIONAL REGULATION OF HUMAN DRUG-METABOLIZING CYTOCHROME P450 ENZYMES Factors Affecting Drug-Metabolizing Cytochromes P450 Transcriptional Regulation of CYP Regulation of Drug-Metabolizing CYPs IMPORTANCE OF PHARMACOGENOMICS Introduction Pharmacogenetic Polymorphisms Polygenic and Multifactorial Aspects of Drug Metabolism Phenotype Genomics Technologies and Approaches Conclusions PART TWO: Metabolism of Drugs INTRODUCTION TO DRUG METABOLISM Introduction Historical Aspects Diversity of Drug Metabolic Pathways Influence of Drug Metabolism on Pharmacological Activity Biotoxification Extrahepatic Drug Metabolism Factors Affecting Drug Metabolism Activity Conclusions CENTRAL NERVOUS SYSTEM DRUGS Introduction Antidepressants Antipsychotics Tranquillizers and Hypnotic Agents Psychostimulants Anticonvulsants and Mood Stabilizers Agents for Dementia and Cognitive Enhancers Antimigraine Drugs Other Drugs Conclusions CARDIOVASCULAR DRUGS Introduction RAAS as a Target for Angiotensin-Converting Enzyme Inhibitors and AT1 Receptor Blockers Adrenergic Receptor Agonists Adrenergic Receptor Antagonists Diuretics Antiarrhythmics Anticoagulants Cholesterol-Lowering Drugs ANTICANCER DRUGS Introduction Alkylating Drugs Platinum-Containing Agents Antimetabolites Endocrine Therapy Histone Deacetylase Inhibitor (Vorinostat) Tyrosine Kinase Inhibitors Proteasome Inhibitor (Bortezomib) ANTIMICROBIAL AGENTS Introduction Pharmacokinetics/Pharmacodynamics of the Main Families of Antimicrobial Agents Pharmacogenetics Conclusions DRUGS AGAINST ACUTE AND CHRONIC PAIN In