In the newly revised second edition of Drug Metabolism Handbook: Concepts and Applications in Cancer Research, a distinguished team of researchers delivers an incisive and robust exploration of the drug metabolism system and a well-illustrated and detailed explanation of the latest tools and techniques used in the research, pharmacology, and medicine. The book discusses the creation of new molecular entities, drug development, troubleshooting, and other highly relevant concepts, guiding readers through new applications in pharmaceutical research, development, and assessment.
The latest edition offers updated content on metabolism basics and the application of a variety of new techniques to cancer treatment, including mass spectrometry, imaging, metabolomics, and immunotherapy. It also offers in-depth case studies highlighting the role of metabolism in drug development.
Readers will also benefit from: - A thorough introduction to drug metabolism, including a historical perspective, factors affecting metabolism, and biotransformations in drug metabolism - Comprehensive discussions of technologies for in vitro and in vivo studies, including mass spectrometry and accelerating metabolite identification with mass spectrometry - In-depth explorations of drug interactions, including discussions of enzyme inhibition and the characterization of cytochrome P450 mechanism-based inhibition - Fulsome treatments of drug toxicity, including the role of drug metabolism in toxicity, and allergic reactions to drugs
Perfect for medicinal chemists, pharmaceutical scientists, and toxicologists, Drug Metabolism Handbook: Concepts and Applications in Cancer Research, Second Edition will also earn a place in the libraries of analytical chemists and drug discovery professionals.
Table of Contents
Volume 1
Preface xiii
List of contributors xv
Part I. Introduction 1
1. Historical Perspective 3
Roberta S. King
1.1 Controversies Spanning Past, Present, and Future 3
1.2 1800s: Discovery of Major Drug Metabolism Pathways (Conti and Bickel, 1977) 5
1.3 1900-1950s: Confirmation of Major Pathways and Mechanistic Studies 8
1.4 1950s-1980: Modern Drug Metabolism Emerges, with Enzymatic Basis 9
1.5 1980-2005: Field Driven by Improved Technologies 10
1.6 2005+: High Technology 10
References 10
2. Factors Affecting Metabolism 13
Roberta S. King
References 16
3. Biotransformations in Drug Metabolism 17
Roberta S. King
3.1 Drug Metabolism in Drug Development and Drug Therapy 17
3.2 Prediction of Metabolite and Enzyme Responsible 20
3.3 Functional Group Biotransformations: Phase I, Phase II, and Catalysis 21
3.4 Oxidations and Cytochrome P450 23
3.5 Enzymology and Modifiers of Cytochrome P450s 34
References 39
4. A Comprehensive Picture of Biotransformation in Drug Discovery 41
Joe R. Cannon, Prakash Vachaspati, and Yang Yuan
4.1 Introduction 41
4.2 Rate of Metabolism 43
4.3 Metabolism of Small Molecules 46
4.4 Analytical Technologies in Drug Metabolism 65
4.5 Biotransformation for Novel Modalities - Peptides and Protein Degraders 79
4.6 Conclusion 93
References 93
5. In Vivo Drug Metabolite Kinetics 103
Zheng Yang
5.1 Introduction 103
5.2 In Vivo Drug Metabolite Kinetic Concepts and Principles 105
5.3 Effect of Inhibition and Induction on Metabolite Kinetics 122
5.4 Determination of Formation and Elimination Clearance of
Metabolite 127
5.5 Incorporation of Pharmacologically Active Metabolite(s) in
Pharmacokinetic/Pharmacodynamic Modeling 130
5.6 Summary 135
Abbreviations 135
References 137
6. LC-MS/MS-Based Proteomics Methods for Quantifying Drug-Metabolizing Enzymes and Transporters 143
Logan S. Smith, Sun Min Jung, Jiapeng Li, and Hao-Jie Zhu
6.1 Introduction 143
6.2 Mass Spectrometry Versus Alternative Protein Quantification Methods 144
6.3 Mass Spectrometry Data Acquisition Methods for Proteomics Analysis 145
6.4 Targeted Approaches 146
6.5 Untargeted Proteomics Approaches 147
6.6 Relative Quantification Versus Absolute Quantification 150
6.7 Label-Based Proteomics 152
6.8 Label-Free Proteomics 155
6.9 DMET Protein Quantification Using LC-MS/MS-Based Proteomics 158
6.10 Potential Application of DMET Expression Studies 160
6.11 Considerations of DMET Protein Quantification Utilizing LC-MS/MS Methods 163
6.12 Conclusion 164
References 164
Part II. Technologies for in vitro and in vivo studies 177
7. Mass Spectrometry 179
Thomas R. Sharp
7.1 Introduction 179
7.2 A Brief History 180
7.3 The Mass Spectrometry Literature 182
7.4 Mass Spectrometry Instrumentation 183
7.5 Interpretation:What Does it Mean 211
7.6 Conclusions 254
References 255
8. Accelerating Metabolite Identification Mass Spectrometry Technology Drives Metabolite Identification Studies Forward 267
Ala F. Nassar
8.1 Introduction 267
8.2 Criteria for LC-MS Methods 269
8.3 Matrices Effect 269
8.4 Tool of Choice for Metabolite Characterization 270
8.5 Strategies for Identifying Unknown Metabolites 274
8.6 Online HD-LC-MS 275
8.7 “All-in-One” Radioactivity Detector, Stop Flow, and Dynamic
Flow for Metabolite Identification 282
8.8 Metabolic Activation Studies by Mass Spectrometry 287
8.9 Strategies to Screen for Reactive Metabolites 288
8.10 Summary 289
Abbreviations and Glossary 290
References 299
9. Role of Structural Modifications of Drug Candidates to Enhance Metabolic Stability 303
Ala F. Nassar
9.1 Background 303
9.2 Introduction 304
9.3 Significance of Metabolite Characterization and Structure Modification 305
9.4 Enhance Metabolic Stability 305
9.5 Metabolic Stability and Intrinsic Metabolic Clearance 306
9.6 Advantages of Enhancing Metabolic Stability 307
9.7 Strategies to Enhance Metabolic Stability 307
9.8 Analytical Tools 317
9.9 Case Studies 318
9.10 Conclusions 320
References 320
10. Drug Design Strategies: Role of Structural Modifications of Drug Candidates to Improve PK Parameters of New Drugs 323
Ala F. Nassar
10.1 Active Metabolites 323
10.2 Oral Absorption and Intravenous Dose 333
10.3 PK Analysis 333
10.4 Case Studies 334
10.5 Prodrugs to IncreaseWater Solubility 338
10.6 Conclusion 339
References 340
11. Chemical Structural Alert and Reactive Metabolite Concept as Applied in Medicinal Chemistry to Minimize the Toxicity of Drug Candidates 345
Ala F. Nassar
11.1 Importance of Reactive Intermediates in Drug Discovery and Development 345
11.2 Idiosyncratic Drug Toxicity and Molecular Mechanisms 349
11.3 Key Tools and Strategies to Improve Drug Safety 352
11.4 Peroxidases 357
11.5 Acyl Glucuronidation and S-Acyl-CoA Thioesters 358
11.6 Covalent Binding 359
11.7 Mechanistic Studies 360
11.8 Preclinical Development 363
11.9 Clinical Development: Strategy 364
11.10 Case Studies 364
11.11 Conclusion and Future Possibilities 366
References 367
12. Studies of Reactive Metabolites using Genotoxicity Arrays and Enzyme/DNA Biocolloids - 2021 373
James F. Rusling and Eli G. Hvastkovs
12.1 Introduction 373
12.2 On Demand Metabolic Reactions 374
12.3 Arrays with Electrochemical Detection 376
12.4 Electrochemiluminescent Arrays 379
12.5 ECL Arrays can Measure Both DNA Oxidation and Nucleobase Adduction 388
12.6 Detecting Site-Specific Damage to TUMOR SUPPRESSORGenes 392
12.7 Emerging Technologies and Methods 394
12.8 Conclusions and Future Outlook 398
Acknowledgments 399
Biographies 399
References 399
Part III. Drug interactions 407
13. Enzyme Inhibition 409
Paul F. Hollenberg
13.1 Introduction 409
13.2 Mechanisms of Enzyme Inhibition 411
13.3 Competitive Inhibition 412
13.4 Noncompetitive Inhibition 413
13.5 Uncompetitive Inhibition 414
13.6 Product Inhibition 414
13.7 Transition-State Analogs 415
13.8 Slow, Tight-Binding Inhibitors 415
13.9 Mechanism-Based Inactivators 415
13.10 Inhibitors that are Metabolized to Reactive Products that Covalently Attach to the Enzyme 418
13.11 Substrate Inhibition 419
13.12 Partial Inhibition 419
13.13 Inhibition of Cytochrome P450 Enzymes 420
13.14 Reversible Inhibitors 421
13.15 Quasi-Irreversible Inhibitors 421
13.16 Mechanism-Based Inactivators 422
References 424
14. Xenobiotic Receptor-Mediated Gene Regulation in Drug Metabolism and Disposition 427
Hongbing Wang and Wen Xie
14.1 Introduction 427
14.2 Pregnane X Receptor 429
14.3 Constitutive Androstane/Activated Receptor (CAR) 441
14.4 Closing Remarks and Perspectives 452
Acknowledgments 453
References 453
15. Characterization of Cytochrome P450 Mechanism Based Inhibition 465
Dan A. Rock and Larry C. Wienkers
15.1 Introduction 465
15.2 Inhibitors that Upon Activation Bind Covalently to the P450 Apoprotein 475
15.3 Inhibitors that Interact in a Pseudoirreversible Manner with Heme Iron 478
15.4 Inactivation that Cause Destruction of the Prosthetic Heme Group, Often Times Leading to Heme-Derived Products that Covalently Modify the Apoprotein 480
References 515
16. An Introduction to Metabolic Reaction-Phenotyping 527
Carl Davis
16.1 Introduction 527
16.2 Significant Drug-Metabolizing Enzymes 528
16.3 Common In VitroMethods to Assess Drug Metabolism 534
16.4 In Vitroto In VivoExtrapolation of Metabolic Clearance 539
16.5 Summary 546
References 546
17. Epigenetic Regulation of Drug-Metabolizing Enzymes in Cancer 553
Jiaqi Wang, Xiaoli Zheng, and Su Zeng
17.1 Introduction 553
17.2 DNA Methylation of DMEs 554
17.3 Histone Modification 558
17.4 Noncoding RNA 559
17.5 RNA Methylation 561
17.6 Closing Remarks and Perspectives 563
Acknowledgments 564
References 564
18. Epigenetic Regulation of Drug Transporters in Cancer 573
Yingying Wang, Ying Zhou, Yu Wang, Lushan Yu, and Su Zeng
18.1 Introduction 573
18.2 DNA Methylation 575
18.3 Histone Modifications 579
18.4 Noncoding RNAs 581
18.5 Closing Remarks and Perspectives 591
Acknowledgments 592
References 592
Volume 2
Preface xi
List of contributors xiii
Part IV. Toxicity 605
19. The Role of Drug Metabolism in Toxicity 607
Umesh M. Hanumegowda and Carl Davis
20. Allergic Reactions to Drugs 677
Mark P. Grillo
21. Chemical Mechanisms in Toxicology 703
Mark P. Grillo
22. Role of Bioactivation Reactions in Chemically Induced Nephrotoxicity 745
Lawrence H. Lash
Part V. Applications 773
23. Mapping the Heterogeneous Distribution of Cancer Drugs by Imaging Mass Spectrometry 775
Purva S. Damale and Shibdas Banerjee
24. Systemic Metabolomic Changes Associated with Chemotherapy: Role in Personalized Therapy 811
Bhargab Kalita, Ganesh K. Barik, Tanisha Sharma, Khushman Taunk, Praneeta P. Bhavsar, Manas K. Santra, and Srikanth Rapole
25. Metabolic Reprogramming in Cancer 841
Debasish Prusty and Soumen Kanti Manna
26. Case Study: Metabolism and Reactions of Alkylating Agents in Cancer Therapy 893
Ala F. Nassar, Adam V. Wisnewski, and Ivan King
27. Rewiring of Drug Metabolism and Its Cross-talk with Metabolic Reprogramming in Cancer 923
Subhabrata Majumder and Soumen Kanti Manna
28. Principles of Drug Metabolism and Interactions in Cardio-Oncology 967
Sherry-Ann Brown, Craig Beavers, Sailaja Kamaraju, Meera Mohan, Olubadewa Fatunde, Gift Echefu, Svetlana Zaharova, Brianna Wallace, and Carolyn Oxencis
Index 993
