Overview

A comprehensive guide to cutting-edge tools in ADME research The last decade has seen tremendous progress in the development of analytical techniques such as mass spectrometry and molecular biology tools, resulting in important advances in drug discovery, particularly in the area of absorption, distribution, metabolism, and excretion (ADME). ADME-Enabling Technologies in Drug Design and Development focuses on the current state of the art in the field, presenting a comprehensive review of the latest tools for generating ADME data in drug discovery. It examines the broadest possible range of available technologies, giving readers the information they need to choose the right tool for a given application, a key requisite for obtaining favorable results in a timely fashion for regulatory filings. With over thirty contributed chapters by an international team of experts, the book provides: A thorough examination of current tools, covering both electronic/mechanical technologies and biologically based ones Coverage of applications for each technology, including key parameters, optimal conditions for intended results, protocols, and case studies Detailed discussion of emerging tools and techniques, from stem cells and genetically modified animal models to imaging technologies Numerous figures and diagrams throughout the text Scientists and researchers in drug metabolism, pharmacology, medicinal chemistry, pharmaceutics, toxicology, and bioanalytical science will find ADME-Enabling Technologies in Drug Design and Development an invaluable guide to the entire drug development process, from discovery to regulatory issues.

Full Product Details

Author:   Donglu Zhang (Bristol-Myers Squibb Pharmaceutical Research Institute) ,  Sekhar Surapaneni
Publisher:   John Wiley & Sons Inc
Imprint:   John Wiley & Sons Inc
Dimensions:   Width: 22.10cm , Height: 3.70cm , Length: 28.70cm
Weight:   1.647kg
ISBN:  

9780470542781

ISBN 10:   0470542780
Pages:   624
Publication Date:   25 May 2012
Audience:   Professional and scholarly ,  Professional & Vocational
Format:   Hardback
Publisher's Status:   Active
Availability:   Out of stock  
The supplier is temporarily out of stock of this item. It will be ordered for you on backorder and shipped when it becomes available.

Table of Contents

FOREWORD xxi Lisa A. Shipley PREFACE xxv Donglu Zhang and Sekhar Surapaneni CONTRIBUTORS xxvii PART A ADME: OVERVIEW AND CURRENT TOPICS 1 1 Regulatory Drug Disposition and NDA Package Including MIST 3 Sekhar Surapaneni 1.1 Introduction 3 1.2 Nonclinical Overview 5 1.3 PK 5 1.4 Absorption 5 1.5 Distribution 6 1.6 Metabolism 7 1.7 Excretion 11 1.8 Impact of Metabolism Information on Labeling 11 1.9 Conclusions 12 References 12 2 Optimal ADME Properties for Clinical Candidate and Investigational New Drug (IND) Package 15 Rajinder Bhardwaj and Gamini Chandrasena 2.1 Introduction 15 2.2 NCE and Investigational New Drug (IND) Package 16 2.3 ADME Optimization 17 2.4 ADME Optimization for CNS Drugs 23 2.5 Summary 24 References 25 3 Drug Transporters in Drug Interactions and Disposition 29 Imad Hanna and Ryan M. Pelis 3.1 Introduction 29 3.2 ABC Transporters 31 3.3 SLC Transporters 33 3.4 In vitro Assays in Drug Development 39 3.5 Conclusions and Perspectives 45 References 46 4 Pharmacological and Toxicological Activity of Drug Metabolites 55 W. Griffith Humphreys 4.1 Introduction 55 4.2 Assessment of Potential for Active Metabolites 56 4.3 Assessment of the Potential Toxicology of Metabolites 59 4.4 Safety Testing of Drug Metabolites 62 4.5 Summary 63 References 63 5 Improving the Pharmaceutical Properties of Biologics in Drug Discovery: Unique Challenges and Enabling Solutions 67 Jiwen Chen and Ashok Dongre 5.1 Introduction 67 5.2 Pharmacokinetics 68 5.3 Metabolism and Disposition 70 5.4 Immunogenicity 71 5.5 Toxicity and Preclinical Assessment 74 5.6 Comparability 74 5.7 Conclusions 75 References 75 6 Clinical Dose Estimation Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation 79 Lingling Guan 6.1 Introduction 79 6.2 Biomarkers in PK and PD 80 6.3 Model-Based Clinical Drug Development 83 6.4 First-in-Human Dose 86 6.5 Examples 89 6.6 Discussion and Conclusion 90 References 93 7 Pharmacogenomics and Individualized Medicine 95 Anthony Y.H. Lu and Qiang Ma 7.1 Introduction 95 7.2 Individual Variability in Drug Therapy 95 7.3 We Are All Human Variants 96 7.4 Origins of Individual Variability in Drug Therapy 96 7.5 Genetic Polymorphism of Drug Targets 97 7.6 Genetic Polymorphism of Cytochrome P450s 98 7.7 Genetic Polymorphism of Other Drug Metabolizing Enzymes 100 7.8 Genetic Polymorphism of Transporters 100 7.9 Pharmacogenomics and Drug Safety 101 7.10 Warfarin Pharmacogenomics: A Model for Individualized Medicine 102 7.11 Can Individualized Drug Therapy Be Achieved? 104 7.12 Conclusions 104 Disclaimer 105 Contact Information 105 References 105 8 Overview of Drug Metabolism and Pharmacokinetics with Applications in Drug Discovery and Development in China 109 Chang-Xiao Liu 8.1 Introduction 109 8.2 PK–PD Translation Research in New Drug Research and Development 109 8.3 Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME/T) Studies in Drug Discovery and Early Stage of Development 110 8.4 Drug Transporters in New Drug Research and Development 111 8.5 Drug Metabolism and PK Studies for New Drug Research and Development 113 8.6 Studies on the PK of Biotechnological Products 117 8.7 Studies on the PK of TCMS 118 8.8 PK and Bioavailability of Nanomaterials 123 References 125 PART B ADME SYSTEMS AND METHODS 129 9 Technical Challenges and Recent Advances of Implementing Comprehensive ADMET Tools in Drug Discovery 131 Jianling Wang and Leslie Bell 9.1 Introduction 131 9.2 “A” Is the First Physiological Barrier That a Drug Faces 131 9.3 “M” Is Frequently Considered Prior to Distribution Due to the “First-Pass” Effect 139 9.4 “D” Is Critical for Correctly Interpreting PK Data 142 9.5 “E”: The Elimination of Drugs Should Not Be Ignored 145 9.6 Metabolism- or Transporter-Related Safety Concerns 146 9.7 Reversible CYP Inhibition 147 9.8 Mechanism-Based (Time-Dependent) CYP Inhibition 149 9.9 CYP Induction 152 9.10 Reactive Metabolites 153 9.11 Conclusion and Outlook 154 Acknowledgments 155 References 155 10 Permeability and Transporter Models in Drug Discovery and Development 161 Praveen V. Balimane, Yong-Hae Han, and Saeho Chong 10.1 Introduction 161 10.2 Permeability Models 162 10.3 Transporter Models 163 10.4 Integrated Permeability–Transporter Screening Strategy 166 References 167 11 Methods for Assessing Blood–Brain Barrier Penetration in Drug Discovery 169 Li Di and Edward H. Kerns 11.1 Introduction 169 11.2 Common Methods for Assessing BBB Penetration 170 11.3 Methods for Determination of Free Drug Concentration in the Brain 170 11.4 Methods for BBB Permeability 172 11.5 Methods for Pgp Efflux Transport 173 11.6 Conclusions 174 References 174 12 Techniques for Determining Protein Binding in Drug Discovery and Development 177 Tom Lloyd 12.1 Introduction 177 12.2 Overview 178 12.3 Equilibrium Dialysis 179 12.4 Ultracentrifugation 180 12.5 Ultrafiltration 181 12.6 Microdialysis 182 12.7 Spectroscopy 182 12.8 Chromatographic Methods 183 12.9 Summary Discussion 183 Acknowledgment 185 References 185 13 Reaction Phenotyping 189 Chun Li and Nataraj Kalyanaraman 13.1 Introduction 189 13.2 Initial Considerations 190 13.3 CYP Reaction Phenotyping 193 13.4 Non-P450 Reaction Phenotyping 199 13.5 UGT Conjugation Reaction Phenotyping 201 13.6 Reaction Phenotyping for Other Conjugation Reactions 204 13.7 Integration of Reaction Phenotyping and Prediction of DDI 205 13.8 Conclusion 205 References 206 14 Fast and Reliable CYP Inhibition Assays 213 Ming Yao, Hong Cai, and Mingshe Zhu 14.1 Introduction 213 14.2 CYP Inhibition Assays in Drug Discovery and Development 215 14.3 HLM Reversible CYP Inhibition Assay Using Individual Substrates 217 14.4 HLM RI Assay Using Multiple Substrates (Cocktail Assays) 222 14.5 Time-Dependent CYP Inhibition Assay 226 14.6 Summary and Future Directions 228 References 230 15 Tools and Strategies for the Assessment of Enzyme Induction in Drug Discovery and Development 233 Adrian J. Fretland, Anshul Gupta, Peijuan Zhu, and Catherine L. Booth-Genthe 15.1 Introduction 233 15.2 Understanding Induction at the Gene Regulation Level 233 15.3 In silico Approaches 234 15.4 In vitro Approaches 235 15.5 In vitro Hepatocyte and Hepatocyte-Like Models 238 15.6 Experimental Techniques for the Assessment of Induction in Cell-Based Assays 239 15.7 Modeling and Simulation and Assessment of Risk 244 15.8 Analysis of Induction in Preclinical Species 245 15.9 Additional Considerations 245 15.10 Conclusion 246 References 246 16 Animal Models for Studying Drug Metabolizing Enzymes and Transporters 253 Kevin L. Salyers and Yang Xu 16.1 Introduction 253 16.2 Animal Models of DMEs 253 16.3 Animal Models of Drug Transporters 263 16.4 Conclusions and the Path Forward 270 Acknowledgments 271 References 271 17 Milk Excretion and Placental Transfer Studies 277 Matthew Hoffmann and Adam Shilling 17.1 Introduction 277 17.2 Compound Characteristics That Affect Placental Transfer and Lacteal Excretion 277 17.3 Study Design 281 17.4 Conclusions 289 References 289 18 Human Bile Collection for ADME Studies 291 Suresh K. Balani, Lisa J. Christopher, and Donglu Zhang 18.1 Introduction 291 18.2 Physiology 291 18.3 Utility of the Biliary Data 292 18.4 Bile Collection Techniques 293 18.5 Future Scope 297 Acknowledgment 297 References 297 PART C ANALYTICAL TECHNOLOGIES 299 19 Current Technology and Limitation of LC-MS 301 Cornelis E.C.A. Hop 19.1 Introduction 301 19.2 Sample Preparation 302 19.3 Chromatography Separation 302 19.4 Mass Spectrometric Analysis 304 19.5 Ionization 304 19.6 MS Mode versus MS/MS or MSn Mode 305 19.7 Mass Spectrometers: Single and Triple Quadrupole Mass Spectrometers 306 19.8 Mass Spectrometers: Three-Dimensional and Linear Ion Traps 308 19.9 Mass Spectrometers: Time-of-Flight Mass Spectrometers 308 19.10 Mass Spectrometers: Fourier Transform and Orbitrap Mass Spectrometers 309 19.11 Role of LC-MS in Quantitative in vitro ADME Studies 309 19.12 Quantitative in vivo ADME Studies 311 19.13 Metabolite Identification 312 19.14 Tissue Imaging by MS 313 19.15 Conclusions and Future Directions 313 References 314 20 Application of Accurate Mass Spectrometry for Metabolite Identification 317 Zhoupeng Zhang and Kaushik Mitra 20.1 Introduction 317 20.2 High-Resolution/Accurate Mass Spectrometers 317 20.3 Postacquisition Data Processing 318 20.4 Utilities of High-Resolution/Accurate Mass Spectrometry (HRMS) in Metabolite Identification 320 20.5 Conclusion 328 References 329 21 Applications of Accelerator Mass Spectrometry (AMS) 331 Xiaomin Wang, Voon Ong, and Mark Seymour 21.1 Introduction 331 21.2 Bioanalytical Methodology 332 References 337 22 Radioactivity Profiling 339 Wing Wah Lam, Jose Silva, and Heng-Keang Lim 22.1 Introduction 339 22.2 Radioactivity Detection Methods 340 22.3 AMS 346 22.4 Intracavity Optogalvanic Spectroscopy 349 22.5 Summary 349 Acknowledgments 349 References 349 23 A Robust Methodology for Rapid Structure Determination of Microgram-Level Drug Metabolites by NMR Spectroscopy 353 Kim A. Johnson, Stella Huang, and Yue-Zhong Shu 23.1 Introduction 353 23.2 Methods 354 23.3 Trazodone and Its Metabolism 355 23.4 Trazodone Metabolite Generation and NMR Sample Preparation 356 23.5 Metabolite Characterization 356 23.6 Comparison with Flow Probe and LC-NMR Methods 361 23.7 Metabolite Quantification by NMR 361 23.8 Conclusion 361 References 362 24 Supercritical Fluid Chromatography 363 Jun Dai, Yingru Zhang, David B. Wang-Iverson, and Adrienne A. Tymiak 24.1 Introduction 363 24.2 Background 363 24.3 SFC Instrumentation and General Considerations 364 24.4 SFC in Drug Discovery and Development 369 24.5 Future Perspective 375 References 376 25 Chromatographic Separation Methods 381 Wenying Jian, Richard W. Edom, Zhongping (John) Lin, and Naidong Weng 25.1 Introduction 381 25.2 LC Separation Techniques 383 25.3 Sample Preparation Techniques 388 25.4 High-Speed LC-MS Analysis 390 25.5 Orthogonal Separation 394 25.6 Conclusions and Perspectives 395 References 396 26 Mass Spectrometric Imaging for Drug Distribution in Tissues 401 Daniel P. Magparangalan, Timothy J. Garrett, Dieter M. Drexler, and Richard A. Yost 26.1 Introduction 401 26.2 MSI Instrumentation 403 26.3 MSI Workfl ow 406 26.4 Applications of MSI for in situ ADMET Tissue Studies 408 26.5 Conclusions 413 References 414 27 Applications of Quantitative Whole-Body Autoradiography (QWBA) in Drug Discovery and Development 419 Lifei Wang, Haizheng Hong, and Donglu Zhang 27.1 Introduction 419 27.2 Equipment and Materials 419 27.3 Study Designs 420 27.4 QWBA Experimental Procedures 420 27.5 Applications of QWBA 421 27.6 Limitations of QWBA 432 References 433 PART D NEW AND RELATED TECHNOLOGIES 435 28 Genetically Modified Mouse Models in ADME Studies 437 Xi-Ling Jiang and Ai-Ming Yu 28.1 Introduction 437 28.2 Drug Metabolizing Enzyme Genetically Modified Mouse Models 438 28.3 Drug Transporter Genetically Modifi ed Mouse Models 442 28.4 Xenobiotic Receptor Genetically Modified Mouse Models 446 28.5 Conclusions 448 References 448 29 Pluripotent Stem Cell Models in Human Drug Development 455 David C. Hay 29.1 Introduction 455 29.2 Human Drug Metabolism and Compound Attrition 455 29.3 Human Hepatocyte Supply 456 29.4 hESCS 456 29.5 hESC HLC Differentiation 456 29.6 iPSCS 456 29.7 CYP P450 Expression in Stem Cell-Derived HLCs 457 29.8 Tissue Culture Microenvironment 457 29.9 Culture Defi nition for Deriving HLCS from Stem Cells 457 29.10 Conclusion 457 References 458 30 Radiosynthesis for ADME Studies 461 Brad D. Maxwell and Charles S. Elmore 30.1 Background and General Requirements 461 30.2 Radiosynthesis Strategies and Goals 463 30.3 Preparation and Synthesis 467 30.4 Analysis and Product Release 469 30.5 Documentation 471 30.6 Summary 471 References 471 31 Formulation Development for Preclinical in vivo Studies 473 Yuan-Hon Kiang, Darren L. Reid, and Janan Jona 31.1 Introduction 473 31.2 Formulation Consideration for the Intravenous Route 473 31.3 Formulation Consideration for the Oral, Subcutaneous, and Intraperitoneal Routes 474 31.4 Special Consideration for the Intraperitoneal Route 475 31.5 Solubility Enhancement 475 31.6 pH Manipulation 476 31.7 Cosolvents Utilization 477 31.8 Complexation 479 31.9 Amorphous Form Approach 479 31.10 Improving the Dissolution Rate 479 31.11 Formulation for Toxicology Studies 479 31.12 Timing and Assessment of Physicochemical Properties 480 31.13 Critical Issues with Solubility and Stability 481 31.14 General and Quick Approach for Formulation Identification at the Early Discovery Stages 482 References 482 32 In vitro Testing of Proarrhythmic Toxicity 485 Haoyu Zeng and Jiesheng Kang 32.1 Objectives, Rationale, and Regulatory Compliance 485 32.2 Study System and Design 486 32.3 Good Laboratory Practice (GLP)-hERG Study 489 32.4 Medium-Throughput Assays Using PatchXpress as a Case Study 490 32.5 Nonfunctional and Functional Assays for hERG Traffi cking 491 32.6 Conclusions and the Path Forward 491 References 492 33 Target Engagement for PK/PD Modeling and Translational Imaging Biomarkers 493 Vanessa N. Barth, Elizabeth M. Joshi, and Matthew D. Silva 33.1 Introduction 493 33.2 Application of LC-MS/MS to Assess Target Engagement 494 33.3 LC-MS/MS-Based RO Study Designs and Their Calculations 494 33.4 Leveraging Target Engagement Data for Drug Discovery from an Absorption, Distribution, Metabolism, and Excretion (ADME) Perspective 497 33.5 Application of LC-MS/MS to Discovery Novel Tracers 502 33.6 Noninvasive Translational Imaging 503 33.7 Conclusions and the Path Forward 507 References 508 34 Applications of iRNA Technologies in Drug Transporters and Drug Metabolizing Enzymes 513 Mingxiang Liao and Cindy Q. Xia 34.1 Introduction 513 34.2 Experimental Designs 514 34.3 Applications of RNAi in Drug Metabolizing Enzymes and Transporters 527 34.4 Conclusions 538 Acknowledgment 539 References 539 Appendix Drug Metabolizing Enzymes and Biotransformation Reactions 545 Natalia Penner, Caroline Woodward, and Chandra Prakash A.1 Introduction 545 A.2 Oxidative Enzymes 547 A.3 Reductive Enzymes 550 A.4 Hydrolytic Enzymes 551 A.5 Conjugative (Phase II) DMEs 553 A.6 Factors Affecting DME Activities 555 A.7 Biotransformation Reactions 557 A.8 Summary 561 Acknowledgment 562 References 562 Index 567

Reviews

<p> This book fills time needs of ADME researchers and provides a fine reference book for scientists engaged in the areas of medicinal chemistry, pharmaceutics, bioanalytical sciences, pharmacology and toxicology in academia and pharmaceutical industry. (British Toxicology Society, 1 July 2013) <p>

?This book fills time needs of ADME researchers and provides a fine reference book for scientists engaged in the areas of medicinal chemistry, pharmaceutics, bioanalytical sciences, pharmacology and toxicology in academia and pharmaceutical industry.? (British Toxicology Society, 1 July 2013)

This book fills time needs of ADME researchers and provides a fine reference book for scientists engaged in the areas of medicinal chemistry, pharmaceutics, bioanalytical sciences, pharmacology and toxicology in academia and pharmaceutical industry. (British Toxicology Society, 1 July 2013)

This book fills time needs of ADME researchers and provides a fine reference book for scientists engaged in the areas of medicinal chemistry, pharmaceutics, bioanalytical sciences, pharmacology and toxicology in academia and pharmaceutical industry. ( British Toxicology Society , 1 July 2013)

Review copy sent on 18.6.12 to BTS Newsletter review

Author Information

Donglu Zhang, PhD, is a Principal Scientist in Pharmaceutical Candidate Optimization at Bristol-Myers Squibb in Princeton, New Jersey. He has published seventy peer-reviewed articles, codiscovered the Mass Defect Filtering technique, and coedited two books. Sekhar Surapaneni, PhD, is Director, DMPK, at Celgene Corporation in New Jersey. He has published extensively in peer-reviewed journals and is a member of ISSX and ACS.

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