Drug Metabolism Handbook

Ala F. Nassar, PhD, is a faculty member at Yale University. He leads and executes ADME-Tox experiments supporting grant projects. He has served on numerous editorial boards and is the editor of the previous edition of Drug Metabolism Handbook: Concepts and Applications and Biotransformation and Metabolite Elucidation of Xenobiotics: Characterization and Identification. Paul F. Hollenberg, PhD, was the Maurice H. Seevers Professor and Chair of Pharmacology at the University of Michigan for more than 20 years. His research focused on the active sites of P450s and their catalytic function. He was cofounder and Associate Editor of Chemical Research in Toxicology and has served on numerous editorial boards and review panels. JoAnn Scatina, PhD has over 30 years of experience in Drug Metabolism and Preclinical Drug Development with leadership roles in both big pharma (Wyeth) and smaller biotech firms. She also provides expert drug development advice as a consultant to biotech and academic institutions. Soumen Kanti Manna, PhD, is an Associate Professor in the Biophysics and Structural Genomics Division of Saha Institute of Nuclear Physics, Kolkata. His doctoral work involved cytochrome P450 and other metalloproteins. His current research activities include unravelling of metabolic reprogramming associated with gene-environment interaction and cancer as well as RNA modification and biomarker discovery. Su Zeng, PhD, is a Professor and Director of Institute of Drug Metabolism and Pharmaceutical Analysis at College of Pharmaceutical Sciences, Zhejiang University. His research focuses on the regulation mechanism of drug ADME-Tox by using epigenetic models, transgenic cells expressing drug metabolizing enzymes, or transporters.

• Volume 1Preface xiiiList of contributors xvPart I. Introduction 11. Historical Perspective 3Roberta S. King1.1 Controversies Spanning Past, Present, and Future 31.2 1800s: Discovery of Major Drug Metabolism Pathways (Conti and Bickel, 1977) 51.3 1900–1950s: Confirmation of Major Pathways and Mechanistic Studies 81.4 1950s–1980: Modern Drug Metabolism Emerges, with Enzymatic Basis 91.5 1980–2005: Field Driven by Improved Technologies 101.6 2005+: High Technology 10References 102. Factors Affecting Metabolism 13Roberta S. KingReferences 163. Biotransformations in Drug Metabolism 17Roberta S. King3.1 Drug Metabolism in Drug Development and Drug Therapy 173.2 Prediction of Metabolite and Enzyme Responsible 203.3 Functional Group Biotransformations: Phase I, Phase II, and Catalysis 213.4 Oxidations and Cytochrome P450 233.5 Enzymology and Modifiers of Cytochrome P450s 34References 394. A Comprehensive Picture of Biotransformation in Drug Discovery 41Joe R. Cannon, Prakash Vachaspati, and Yang Yuan4.1 Introduction 414.2 Rate of Metabolism 434.3 Metabolism of Small Molecules 464.4 Analytical Technologies in Drug Metabolism 654.5 Biotransformation for Novel Modalities – Peptides and Protein Degraders 794.6 Conclusion 93References 935. In Vivo Drug Metabolite Kinetics 103Zheng Yang5.1 Introduction 1035.2 In Vivo Drug Metabolite Kinetic Concepts and Principles 1055.3 Effect of Inhibition and Induction on Metabolite Kinetics 1225.4 Determination of Formation and Elimination Clearance ofMetabolite 1275.5 Incorporation of Pharmacologically Active Metabolite(s) inPharmacokinetic/Pharmacodynamic Modeling 1305.6 Summary 135Abbreviations 135References 1376. LC-MS/MS-Based Proteomics Methods for Quantifying Drug-Metabolizing Enzymes and Transporters 143Logan S. Smith, Sun Min Jung, Jiapeng Li, and Hao-Jie Zhu6.1 Introduction 1436.2 Mass Spectrometry Versus Alternative Protein Quantification Methods 1446.3 Mass Spectrometry Data Acquisition Methods for Proteomics Analysis 1456.4 Targeted Approaches 1466.5 Untargeted Proteomics Approaches 1476.6 Relative Quantification Versus Absolute Quantification 1506.7 Label-Based Proteomics 1526.8 Label-Free Proteomics 1556.9 DMET Protein Quantification Using LC-MS/MS-Based Proteomics 1586.10 Potential Application of DMET Expression Studies 1606.11 Considerations of DMET Protein Quantification Utilizing LC-MS/MS Methods 1636.12 Conclusion 164References 164Part II. Technologies for in vitro and in vivo studies 1777. Mass Spectrometry 179Thomas R. Sharp7.1 Introduction 1797.2 A Brief History 1807.3 The Mass Spectrometry Literature 1827.4 Mass Spectrometry Instrumentation 1837.5 Interpretation:What Does it Mean 2117.6 Conclusions 254References 2558. Accelerating Metabolite Identification Mass Spectrometry Technology Drives Metabolite Identification Studies Forward 267Ala F. Nassar8.1 Introduction 2678.2 Criteria for LC-MS Methods 2698.3 Matrices Effect 2698.4 Tool of Choice for Metabolite Characterization 2708.5 Strategies for Identifying Unknown Metabolites 2748.6 Online HD-LC-MS 2758.7 “All-in-One” Radioactivity Detector, Stop Flow, and DynamicFlow for Metabolite Identification 2828.8 Metabolic Activation Studies by Mass Spectrometry 2878.9 Strategies to Screen for Reactive Metabolites 2888.10 Summary 289Abbreviations and Glossary 290References 2999. Role of Structural Modifications of Drug Candidates to Enhance Metabolic Stability 303Ala F. Nassar9.1 Background 3039.2 Introduction 3049.3 Significance of Metabolite Characterization and Structure Modification 3059.4 Enhance Metabolic Stability 3059.5 Metabolic Stability and Intrinsic Metabolic Clearance 3069.6 Advantages of Enhancing Metabolic Stability 3079.7 Strategies to Enhance Metabolic Stability 3079.8 Analytical Tools 3179.9 Case Studies 3189.10 Conclusions 320References 32010. Drug Design Strategies: Role of Structural Modifications of Drug Candidates to Improve PK Parameters of New Drugs 323Ala F. Nassar10.1 Active Metabolites 32310.2 Oral Absorption and Intravenous Dose 33310.3 PK Analysis 33310.4 Case Studies 33410.5 Prodrugs to IncreaseWater Solubility 33810.6 Conclusion 339References 34011. Chemical Structural Alert and Reactive Metabolite Concept as Applied in Medicinal Chemistry to Minimize the Toxicity of Drug Candidates 345Ala F. Nassar11.1 Importance of Reactive Intermediates in Drug Discovery and Development 34511.2 Idiosyncratic Drug Toxicity and Molecular Mechanisms 34911.3 Key Tools and Strategies to Improve Drug Safety 35211.4 Peroxidases 35711.5 Acyl Glucuronidation and S-Acyl-CoA Thioesters 35811.6 Covalent Binding 35911.7 Mechanistic Studies 36011.8 Preclinical Development 36311.9 Clinical Development: Strategy 36411.10 Case Studies 36411.11 Conclusion and Future Possibilities 366References 36712. Studies of Reactive Metabolites using Genotoxicity Arrays and Enzyme/DNA Biocolloids – 2021 373James F. Rusling and Eli G. Hvastkovs12.1 Introduction 37312.2 On Demand Metabolic Reactions 37412.3 Arrays with Electrochemical Detection 37612.4 Electrochemiluminescent Arrays 37912.5 ECL Arrays can Measure Both DNA Oxidation and Nucleobase Adduction 38812.6 Detecting Site-Specific Damage to TUMOR SUPPRESSORGenes 39212.7 Emerging Technologies and Methods 39412.8 Conclusions and Future Outlook 398Acknowledgments 399Biographies 399References 399Part III. Drug interactions 40713. Enzyme Inhibition 409Paul F. Hollenberg13.1 Introduction 40913.2 Mechanisms of Enzyme Inhibition 41113.3 Competitive Inhibition 41213.4 Noncompetitive Inhibition 41313.5 Uncompetitive Inhibition 41413.6 Product Inhibition 41413.7 Transition-State Analogs 41513.8 Slow, Tight-Binding Inhibitors 41513.9 Mechanism-Based Inactivators 41513.10 Inhibitors that are Metabolized to Reactive Products that Covalently Attach to the Enzyme 41813.11 Substrate Inhibition 41913.12 Partial Inhibition 41913.13 Inhibition of Cytochrome P450 Enzymes 42013.14 Reversible Inhibitors 42113.15 Quasi-Irreversible Inhibitors 42113.16 Mechanism-Based Inactivators 422References 42414. Xenobiotic Receptor-Mediated Gene Regulation in Drug Metabolism and Disposition 427Hongbing Wang and Wen Xie14.1 Introduction 42714.2 Pregnane X Receptor 42914.3 Constitutive Androstane/Activated Receptor (CAR) 44114.4 Closing Remarks and Perspectives 452Acknowledgments 453References 45315. Characterization of Cytochrome P450 Mechanism Based Inhibition 465Dan A. Rock and Larry C. Wienkers15.1 Introduction 46515.2 Inhibitors that Upon Activation Bind Covalently to the P450 Apoprotein 47515.3 Inhibitors that Interact in a Pseudoirreversible Manner with Heme Iron 47815.4 Inactivation that Cause Destruction of the Prosthetic Heme Group, Often Times Leading to Heme-Derived Products that Covalently Modify the Apoprotein 480References 51516. An Introduction to Metabolic Reaction-Phenotyping 527Carl Davis16.1 Introduction 52716.2 Significant Drug-Metabolizing Enzymes 52816.3 Common In VitroMethods to Assess Drug Metabolism 53416.4 In Vitroto In VivoExtrapolation of Metabolic Clearance 53916.5 Summary 546References 54617. Epigenetic Regulation of Drug-Metabolizing Enzymes in Cancer 553Jiaqi Wang, Xiaoli Zheng, and Su Zeng17.1 Introduction 55317.2 DNA Methylation of DMEs 55417.3 Histone Modification 55817.4 Noncoding RNA 55917.5 RNA Methylation 56117.6 Closing Remarks and Perspectives 563Acknowledgments 564References 56418. Epigenetic Regulation of Drug Transporters in Cancer 573Yingying Wang, Ying Zhou, Yu Wang, Lushan Yu, and Su Zeng18.1 Introduction 57318.2 DNA Methylation 57518.3 Histone Modifications 57918.4 Noncoding RNAs 58118.5 Closing Remarks and Perspectives 591Acknowledgments 592References 592Volume 2Preface xiList of contributors xiiiPart IV. Toxicity 60519. The Role of Drug Metabolism in Toxicity 607Umesh M. Hanumegowda and Carl Davis20. Allergic Reactions to Drugs 677Mark P. Grillo21. Chemical Mechanisms in Toxicology 703Mark P. Grillo22. Role of Bioactivation Reactions in Chemically Induced Nephrotoxicity 745Lawrence H. LashPart V. Applications 77323. Mapping the Heterogeneous Distribution of Cancer Drugs by Imaging Mass Spectrometry 775Purva S. Damale and Shibdas Banerjee24. Systemic Metabolomic Changes Associated with Chemotherapy: Role in Personalized Therapy 811Bhargab Kalita, Ganesh K. Barik, Tanisha Sharma, Khushman Taunk, Praneeta P. Bhavsar, Manas K. Santra, and Srikanth Rapole25. Metabolic Reprogramming in Cancer 841Debasish Prusty and Soumen Kanti Manna26. Case Study: Metabolism and Reactions of Alkylating Agents in Cancer Therapy 893Ala F. Nassar, Adam V. Wisnewski, and Ivan King27. Rewiring of Drug Metabolism and Its Cross-talk with Metabolic Reprogramming in Cancer 923Subhabrata Majumder and Soumen Kanti Manna28. Principles of Drug Metabolism and Interactions in Cardio-Oncology 967Sherry-Ann Brown, Craig Beavers, Sailaja Kamaraju, Meera Mohan, Olubadewa Fatunde, Gift Echefu, Svetlana Zaharova, Brianna Wallace, and Carolyn OxencisIndex 993