Drug Metabolism Handbook Concepts and Applications

by Nassar, Ala F.

• ISBN13: 9780470118030
• ISBN10: 0470118032
• Edition: 1st
• Format: Hardcover
• Copyright: 2009-02-12
• Publisher: Wiley

Summary

Explains All the Latest Tools and Technologies in Drug Metabolism

Author Biography

Ala F. Nassar, PhD, provides technical and operational leadership in characterizing in vitro and in vivo metabolites. His research focuses on understanding how structure modification can improve the ADME profile for new chemical entities as they advance towards clinical candidacy. Recently, he identified and patented pharmacologically active metabolites of Nexavar®. Dr. Nassar serves on the Editorial Board of Drug Metabolism Letters and The Open Drug Metabolism Journal and is also a reviewer for several other journals.

Paul F. Hollenberg, PhD, is Maurice H. Seevers Collegiate Professor and Chair of Pharmacologyat The University of Michigan. His current research focuses on the relationship between thestructures of the active sites of cytochrome P450s and their catalytic function. Dr. Hollenbergwas cofounder and Associate Editor of Chemical Research in Toxicology and has served onnumerous editorial boards and review panels.

Joann Scatina, PhD, has over twenty-four years of drug metabolism experience, and is currentlyVice President of the Drug Metabolism Division, Drug Safety and Metabolism, for WyethResearch. Dr. Scatina's research interests include identification of metabolites, metabolicpathways and enzymes responsible, in vitro-in vivo extrapolation, and prediction of druginteractions. She is a member of the American Society for Pharmacology and ExperimentalTherapeutics and the International Society for the Study of Xenobiotics (ISSX) and is currentlyserving on the Editorial Board of Drug Metabolism Reviews.

Table of Contents

Preface	p. xiii
List of Contributors	p. xv
Introduction	p. 1
Historical Perspective	p. 3
Controversies Spanning Past, Present, and Future	p. 3
1800s: Discovery of Major Drug Metabolism Pathways (Conti and Bickel, 1977)	p. 4
1900-1950s: Confirmation of Major Pathways and Mechanistic Studies	p. 7
1950s-1980: Modern Drug Metabolism Emerges, with Enzymatic Basis	p. 8
1980-2005: Field Driven by Improved Technologies	p. 9
2005+: High Technology	p. 9
Acknowledgments	p. 10
References	p. 10
Factors Affecting Metabolism	p. 13
Biotransformations in Drug Metabolism	p. 17
Drug Metabolism in Drug Development and Drug Therapy	p. 17
Prediction of Metabolite and Responsible Enzyme	p. 20
Functional Group Biotransformations: Phase I, Phase II, Catalysis	p. 20
Oxidations and Cytochrome P450	p. 23
Enzymology and Modifiers of CYPs	p. 34
References	p. 38
In Vivo Metabolite Kinetics	p. 41
Introduction	p. 41
In Vivo Metabolite Kinetic Concepts and Principles	p. 42
Effect of Inhibition and Induction on Metabolite Kinetics	p. 55
Determination of Formation and Elimination Clearance of Metabolite	p. 60
Summary	p. 62
Acknowledgments	p. 62
References	p. 62
Pharmacogenetics and Pharmacogenomics	p. 65
Introduction: Pharmacogenetics and Pharmacogenomics	p. 65
Pharmacogenomics of Drug-Metabolizing Enzymes (DME)	p. 66
Polymorphisms in Genes Encoding DME and Implications for Drug Discovery and Development	p. 67
Applications of Genetics and Genomics in Drug Discovery and Development	p. 75
References	p. 77
Introduction to Drug Transporters	p. 89
Introduction	p. 89
Transporter Classification, Localization, and Functions	p. 89
Clinical Drug-Drug Interactions	p. 99
Polymorphisms and Regulation of Drug Transporters	p. 106
In Vitro Methods in Evaluation of Drug Transporters	p. 107
Transporters-Drug-Metabolizing Enzymes Interplay	p. 109
Outlook	p. 110
References	p. 111
Technologies for in Vitro and in Vivo Studies	p. 127
Automated Drug Screening for ADMET Properties	p. 129
Introduction	p. 129
Background	p. 129
Modern Laboratory Automation: Origins in Admet	p. 132
Computational Chemistry 101: The Lipinski Rules	p. 134
Automated Methods for Determining log P/log D	p. 135
Drug Solubility	p. 137
Drug Permeability	p. 141
Drug Transporters in Intestinal Absorption	p. 146
Drug Metabolism	p. 147
Plasma Protein Binding	p. 158
QC-QA Considerations	p. 160
Summary	p. 161
References	p. 162
Mass Spectrometry	p. 167
Introduction	p. 167
A Brief History	p. 168
General Background in Mass Spectrometry	p. 170
Instrumentation	p. 172
Inlet Systems: Getting Samples In	p. 173
Ionization Methods: Making Ions	p. 179
Mass Analysis: Sorting by Size	p. 188
Detection: Seeing What Has Been Generated	p. 190
Interpretation of Mass Spectral Data	p. 192
References	p. 221
Approaches to Performing Metabolite Elucidation: One Key to Success in Drug Discovery and Development	p. 229
Introduction	p. 229
Criteria for LC-MS Methods	p. 231
Matrices Effect	p. 231
Metabolite Characterization	p. 232
Strategies for Identifying Unknown Metabolites	p. 235
"All-in-One" Radioactivity Detector, Stop Flow, and Dynamic Flow for Metabolite Identification	p. 242
Strategies to Screen for Reactive Metabolites	p. 247
Summary	p. 248
References	p. 249
Structural Modifications of Drug Candidates: How Useful Are They in Improving Metabolic Stability of New Drugs? Part I: Enhancing Metabolic Stability	p. 253
Background	p. 253
Introduction	p. 254
Significance of Metabolite Characterization and Structure Modification	p. 255
Part I: Enhance Metabolic Stability	p. 255
Metabolic Stability and Intrinsic Metabolic Clearance	p. 256
Advantages of Enhancing Metabolic Stability	p. 257
Strategies to Enhance Metabolic Stability	p. 257
Conclusions	p. 265
References	p. 266
Structural Modifications of Drug Candidates: How Useful Are They in Improving PK Parameters of New Drugs? Part II: Drug Design Strategies	p. 269
Introduction	p. 269
Active Metabolites	p. 269
Prodrugs	p. 273
Hard and Soft Drugs	p. 274
PK Parameters	p. 275
PK Analysis	p. 278
Conclusions	p. 278
References	p. 280
Minimizing the Potential for Drug Bioactivation of Drug Candidates to Success in Clinical Development	p. 283
Introduction	p. 283
Idiosyncratic Drug Toxicity and Molecular Mechanisms	p. 287
Key Tools and Strategies to Improve Drug Safetly	p. 290
Peroxidases	p. 295
Acyl Glucuronidation and S-acyl-CoA Thioesters	p. 295
Covalent Binding	p. 296
Mechanistic Studies	p. 298
Preclinical Development	p. 300
Clinical Development: Strategy	p. 301
Conclusion and Future Possibilities	p. 302
References	p. 302
Screening for Reactive Metabolites Using Genotoxicity Arrays and Enzyme/DNA Biocolloids	p. 307
Introduction	p. 307
Electrochemical and Electrochemiluminescent Arrays	p. 310
DNA/Enzyme Biocolloids for LC-MS Toxicity Screening	p. 318
Alternative Arrays and Other Novel Approaches	p. 325
Summary and Future Outlook	p. 332
References	p. 333
Drug Interactions	p. 341
Enzyme Inhibition	p. 343
Introduction	p. 343
Mechanisms of Enzyme Inhibition	p. 345
Competitive Inhibition	p. 345
Noncompetitive Inhibition	p. 347
Uncompetitive Inhibition	p. 348
Product Inhibition	p. 348
Transition-State Analogs	p. 348
Slow, Tight-Binding Inhibitors	p. 349
Mechanism-Based Inactivators	p. 349
Inhibitors That Are Metabolized to Reactive Products That Covalently Attach to the Enzyme	p. 352
Substrate Inhibition	p. 352
Partial Inhibition	p. 353
Inhibition of Cytochrome P450 Enzymes	p. 353
Reversible Inhibitors	p. 354
Quasi-Irreversible Inhibitors	p. 355
Mechanism-Based Inactivators	p. 356
References	p. 357
Evaluating and Predicting Human Cytochrome P450 Enzyme Induction	p. 359
Introduction	p. 359
Receptor-Based In Vitro Bioassays	p. 361
Immortalized Hepatocytes	p. 364
HepG2 and HepG2-Derived Cell Lines	p. 364
HBG-BC2	p. 365
Hepatocarcinoma-Derived Cell Line: HepaRG	p. 366
Cells of Intestinal Origin: LS180 and Caco-2	p. 366
Immortalized Human Hepatocyte Cell Lines: Fa2N-4	p. 367
Other Immortalized Hepatocyte Cell Lines	p. 368
Primary Human Hepatocyte Culture Systems	p. 368
Interpretation and Quantitative Prediction of Enzyme Induction	p. 373
Clinical Drug Interaction Studies	p. 375
Industrial and Regulatory Perspectives	p. 377
Future Models	p. 378
Conclusions	p. 380
Acknowledgments	p. 381
References	p. 381
An Introduction to Metabolic Reaction Phenotyping	p. 391
Introduction	p. 391
Drug Metabolism	p. 391
Objectives of Reaction Phenotyping in Drug Discovery	p. 393
Metabolic Stability Screening	p. 393
Drug-Metabolizing Enzymes	p. 394
Assay Optimization for Metabolic Clearance and Reaction-Phenotyping Studies	p. 404
In Vitro to In Vivo Extrapolation of Metabolic Clearance	p. 413
In Vitro to In Vivo Extrapolation and Physiological Models of Hepatic Clearance	p. 419
Summary	p. 435
Acknowledgment	p. 436
References	p. 436
Further Reading	p. 446
Nuclear Receptor-Mediated Gene Regulation in Drug Metabolism	p. 449
Introduction	p. 449
Pregnane X Receptor	p. 451
Constitutive Androstane/Activated Receptor (CAR)	p. 461
Aryl Hydrocarbon Receptor (AhR)	p. 470
Closing Remarks and Perspectives	p. 470
Acknowledgments	p. 471
References	p. 471
Characterization of Cytochrome P450 Mechanism-Based Inhibition	p. 479
Introduction	p. 479
Inhibitors That upon Activation, Bind Covalently to the P450 Apoprotein	p. 488
Inhibitors That Interact in a Pseudo-Irreversible Manner with Heme Iron	p. 489
Inhibitors That Cause Destruction of the Prosthetic Heme Group, Oftentimes Leading to Heme-Derived Products That Covalently Modify the Apoprotein	p. 491
References	p. 524
Clinical Drug-Drug Interactions	p. 535
Introduction	p. 535
Mechanisms of DDIs	p. 537
Avoiding DDI	p. 543
References	p. 543
Further Reading	p. 546
Pharmaceutical Excipients in Drug-Drug Interaction	p. 547
Introduction	p. 547
Interaction of Pharmaceutical Excipients with Cytochrome P450s (CYPs)	p. 548
Interaction of Pharmaceutical Excipients with Transporters	p. 552
Summary	p. 554
References	p. 555
Toxicity	p. 559
The Role of Drug Metabolism in Toxicity	p. 561
Introduction	p. 561
Drug-Metabolizing Enzymes	p. 562
Classification of Toxicity	p. 581
Molecular Mechanisms of Toxicity	p. 582
Organ Systems Toxicology	p. 588
Carcinogenesis	p. 599
Teratogenesis	p. 601
Abrogation/Mitigation of Bioactivation-Case Examples	p. 602
Experimental Methods for Screening	p. 605
Summary	p. 606
Acknowledgment	p. 608
References	p. 608
Allergic Reactions to Drugs	p. 629
Introduction	p. 629
Immune System: A Brief Overview	p. 630
Drug Metabolism and the Hapten Hypothesis	p. 631
Allergic Reactions to Drugs (Examples)	p. 632
Conclusions	p. 644
Acknowledgments	p. 646
References	p. 646
Chemical Mechanisms in Toxicology	p. 655
Introduction	p. 655
Glutathione Adducts	p. 659
Covalent Binding	p. 662
Structural Alerts	p. 663
Examples of Metabolic Activation	p. 664
Conclusions	p. 685
Acknowledgments	p. 687
References	p. 687
Mechanisms of Reproductive Toxicity	p. 697
Introduction	p. 697
Overview-Female Reproduction	p. 698
Overview-Male Reproduction	p. 701
Sites of Targeting and Outcomes	p. 704
Effects of Specific Chemicals	p. 708
Translational Applications	p. 721
Conclusions and Future Directions	p. 723
References	p. 724
An Introduction to Toxicogenomics	p. 737
Introduction	p. 737
Microarrays: Genomics-Based Methods for Transcriptional Profiling	p. 737
Chemical Classification-Identifying Chemically Induced Signatures and Their Potential Use in Risk Assessment	p. 738
Experimental Designs of Microarray-Based Technologies	p. 744
The Interpretation and Analysis of Data Generated by Microarray Methodologies	p. 747
Four Basic Microarray-Based Approaches	p. 748
Informatics Tools Utilized by These Informatics Approaches	p. 755
Conclusion	p. 755
References	p. 756
Role of Bioactivation Reactions in Chemically Induced Nephrotoxicity	p. 761
Overview of Renal Structure and Function: Toxicological Implications	p. 761
Interorgan and Intra-renal Bioactivation Pathways	p. 762
Cytochrome P450 (CYP)-Dependent Bioactivation in Renal Proximal Tubular Cells	p. 765
Flavin-Containing Monooxygenase (FMO)-Dependent Bioactivation in Renal Proximal Tubular Cells	p. 767
Renal Bioactivation of Cysteine Conjugates: GSH Conjugation as a Bioactivation Rather Than a Detoxication Pathway	p. 768
Renal Bioactivation of Acetaminophen	p. 775
Summary and Conclusions	p. 776
References	p. 777
Regulatory Perspectives	p. 783
Drug Metabolism in Regulatory Guidances, Clinical Trials, and Product Labeling	p. 785
Introduction	p. 785
The Regulatory Environment	p. 786
Background Information in Regulatory Guidances	p. 795
Nonclinical Guidances and Early-Stage Drug Development	p. 798
Clinical Guidances and Clinical Trials	p. 858
Biologics	p. 948
Miscellaneous Topics	p. 955
Product Labeling	p. 959
Procedural Guidances	p. 974
Initiatives from Regulatory Agencies	p. 980
Summary	p. 982
References	p. 982
Index	p. 1001
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