{"product_id":"adme-enabling-technologies-in-drug-design-and-development-isbn-9780470542781","title":"ADME-Enabling Technologies in Drug Design and Development","description":"\u003cp\u003eA comprehensive guide to cutting-edge tools in ADME research\u003c\/p\u003e \u003cp\u003eThe 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).\u003c\/p\u003e \u003cp\u003eADME-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:\u003c\/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eA thorough examination of current tools, covering both electronic\/mechanical technologies and biologically based ones\u003c\/p\u003e \u003c\/li\u003e \u003cli\u003e \u003cp\u003eCoverage of applications for each technology, including key parameters, optimal conditions for intended results, protocols, and case studies\u003c\/p\u003e \u003c\/li\u003e \u003cli\u003e \u003cp\u003eDetailed discussion of emerging tools and techniques, from stem cells and genetically modified animal models to imaging technologies\u003c\/p\u003e \u003c\/li\u003e \u003cli\u003e \u003cp\u003eNumerous figures and diagrams throughout the text\u003c\/p\u003e \u003c\/li\u003e \u003c\/ul\u003e \u003cp\u003eScientists 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.\u003c\/p\u003e \u003cp\u003eFOREWORD xxi\u003cbr\u003e\u003ci\u003eLisa A. Shipley\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003ePREFACE xxv\u003cbr\u003e\u003ci\u003eDonglu Zhang and Sekhar Surapaneni\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eCONTRIBUTORS xxvii\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART A ADME: OVERVIEW AND CURRENT TOPICS 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 Regulatory Drug Disposition and NDA Package Including MIST 3\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSekhar Surapaneni\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Introduction 3\u003c\/p\u003e \u003cp\u003e1.2 Nonclinical Overview 5\u003c\/p\u003e \u003cp\u003e1.3 PK 5\u003c\/p\u003e \u003cp\u003e1.4 Absorption 5\u003c\/p\u003e \u003cp\u003e1.5 Distribution 6\u003c\/p\u003e \u003cp\u003e1.6 Metabolism 7\u003c\/p\u003e \u003cp\u003e1.7 Excretion 11\u003c\/p\u003e \u003cp\u003e1.8 Impact of Metabolism Information on Labeling 11\u003c\/p\u003e \u003cp\u003e1.9 Conclusions 12\u003c\/p\u003e \u003cp\u003eReferences 12\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 Optimal ADME Properties for Clinical Candidate and Investigational New Drug (IND) Package 15\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eRajinder Bhardwaj and Gamini Chandrasena\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Introduction 15\u003c\/p\u003e \u003cp\u003e2.2 NCE and Investigational New Drug (IND) Package 16\u003c\/p\u003e \u003cp\u003e2.3 ADME Optimization 17\u003c\/p\u003e \u003cp\u003e2.4 ADME Optimization for CNS Drugs 23\u003c\/p\u003e \u003cp\u003e2.5 Summary 24\u003c\/p\u003e \u003cp\u003eReferences 25\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Drug Transporters in Drug Interactions and Disposition 29\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eImad Hanna and Ryan M. Pelis\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Introduction 29\u003c\/p\u003e \u003cp\u003e3.2 ABC Transporters 31\u003c\/p\u003e \u003cp\u003e3.3 SLC Transporters 33\u003c\/p\u003e \u003cp\u003e3.4 In vitro Assays in Drug Development 39\u003c\/p\u003e \u003cp\u003e3.5 Conclusions and Perspectives 45\u003c\/p\u003e \u003cp\u003eReferences 46\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Pharmacological and Toxicological Activity of Drug Metabolites 55\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eW. Griffith Humphreys\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 55\u003c\/p\u003e \u003cp\u003e4.2 Assessment of Potential for Active Metabolites 56\u003c\/p\u003e \u003cp\u003e4.3 Assessment of the Potential Toxicology of Metabolites 59\u003c\/p\u003e \u003cp\u003e4.4 Safety Testing of Drug Metabolites 62\u003c\/p\u003e \u003cp\u003e4.5 Summary 63\u003c\/p\u003e \u003cp\u003eReferences 63\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Improving the Pharmaceutical Properties of Biologics in Drug Discovery: Unique Challenges and Enabling Solutions 67\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eJiwen Chen and Ashok Dongre\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 67\u003c\/p\u003e \u003cp\u003e5.2 Pharmacokinetics 68\u003c\/p\u003e \u003cp\u003e5.3 Metabolism and Disposition 70\u003c\/p\u003e \u003cp\u003e5.4 Immunogenicity 71\u003c\/p\u003e \u003cp\u003e5.5 Toxicity and Preclinical Assessment 74\u003c\/p\u003e \u003cp\u003e5.6 Comparability 74\u003c\/p\u003e \u003cp\u003e5.7 Conclusions 75\u003c\/p\u003e \u003cp\u003eReferences 75\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Clinical Dose Estimation Using Pharmacokinetic\/Pharmacodynamic Modeling and Simulation 79\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eLingling Guan\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 79\u003c\/p\u003e \u003cp\u003e6.2 Biomarkers in PK and PD 80\u003c\/p\u003e \u003cp\u003e6.3 Model-Based Clinical Drug Development 83\u003c\/p\u003e \u003cp\u003e6.4 First-in-Human Dose 86\u003c\/p\u003e \u003cp\u003e6.5 Examples 89\u003c\/p\u003e \u003cp\u003e6.6 Discussion and Conclusion 90\u003c\/p\u003e \u003cp\u003eReferences 93\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Pharmacogenomics and Individualized Medicine 95\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAnthony Y.H. Lu and Qiang Ma\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 95\u003c\/p\u003e \u003cp\u003e7.2 Individual Variability in Drug Therapy 95\u003c\/p\u003e \u003cp\u003e7.3 We Are All Human Variants 96\u003c\/p\u003e \u003cp\u003e7.4 Origins of Individual Variability in Drug Therapy 96\u003c\/p\u003e \u003cp\u003e7.5 Genetic Polymorphism of Drug Targets 97\u003c\/p\u003e \u003cp\u003e7.6 Genetic Polymorphism of Cytochrome P450s 98\u003c\/p\u003e \u003cp\u003e7.7 Genetic Polymorphism of Other Drug Metabolizing Enzymes 100\u003c\/p\u003e \u003cp\u003e7.8 Genetic Polymorphism of Transporters 100\u003c\/p\u003e \u003cp\u003e7.9 Pharmacogenomics and Drug Safety 101\u003c\/p\u003e \u003cp\u003e7.10 Warfarin Pharmacogenomics: A Model for Individualized Medicine 102\u003c\/p\u003e \u003cp\u003e7.11 Can Individualized Drug Therapy Be Achieved? 104\u003c\/p\u003e \u003cp\u003e7.12 Conclusions 104\u003c\/p\u003e \u003cp\u003eDisclaimer 105\u003c\/p\u003e \u003cp\u003eContact Information 105\u003c\/p\u003e \u003cp\u003eReferences 105\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Overview of Drug Metabolism and Pharmacokinetics with Applications in Drug Discovery and Development in China 109\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eChang-Xiao Liu\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 109\u003c\/p\u003e \u003cp\u003e8.2 PK–PD Translation Research in New Drug Research and Development 109\u003c\/p\u003e \u003cp\u003e8.3 Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADME\/T) Studies in Drug Discovery and Early Stage of Development 110\u003c\/p\u003e \u003cp\u003e8.4 Drug Transporters in New Drug Research and Development 111\u003c\/p\u003e \u003cp\u003e8.5 Drug Metabolism and PK Studies for New Drug Research and Development 113\u003c\/p\u003e \u003cp\u003e8.6 Studies on the PK of Biotechnological Products 117\u003c\/p\u003e \u003cp\u003e8.7 Studies on the PK of TCMS 118\u003c\/p\u003e \u003cp\u003e8.8 PK and Bioavailability of Nanomaterials 123\u003c\/p\u003e \u003cp\u003eReferences 125\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART B ADME SYSTEMS AND METHODS 129\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Technical Challenges and Recent Advances of Implementing Comprehensive ADMET Tools in Drug Discovery 131\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eJianling Wang and Leslie Bell\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction 131\u003c\/p\u003e \u003cp\u003e9.2 “A” Is the First Physiological Barrier That a Drug Faces 131\u003c\/p\u003e \u003cp\u003e9.3 “M” Is Frequently Considered Prior to Distribution Due to the “First-Pass” Effect 139\u003c\/p\u003e \u003cp\u003e9.4 “D” Is Critical for Correctly Interpreting PK Data 142\u003c\/p\u003e \u003cp\u003e9.5 “E”: The Elimination of Drugs Should Not Be Ignored 145\u003c\/p\u003e \u003cp\u003e9.6 Metabolism- or Transporter-Related Safety Concerns 146\u003c\/p\u003e \u003cp\u003e9.7 Reversible CYP Inhibition 147\u003c\/p\u003e \u003cp\u003e9.8 Mechanism-Based (Time-Dependent) CYP Inhibition 149\u003c\/p\u003e \u003cp\u003e9.9 CYP Induction 152\u003c\/p\u003e \u003cp\u003e9.10 Reactive Metabolites 153\u003c\/p\u003e \u003cp\u003e9.11 Conclusion and Outlook 154\u003c\/p\u003e \u003cp\u003eAcknowledgments 155\u003c\/p\u003e \u003cp\u003eReferences 155\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Permeability and Transporter Models in Drug Discovery and Development 161\u003cbr\u003e\u003c\/b\u003e\u003ci\u003ePraveen V. Balimane, Yong-Hae Han, and Saeho Chong\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction 161\u003c\/p\u003e \u003cp\u003e10.2 Permeability Models 162\u003c\/p\u003e \u003cp\u003e10.3 Transporter Models 163\u003c\/p\u003e \u003cp\u003e10.4 Integrated Permeability–Transporter Screening Strategy 166\u003c\/p\u003e \u003cp\u003eReferences 167\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Methods for Assessing Blood–Brain Barrier Penetration in Drug Discovery 169\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eLi Di and Edward H. Kerns\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 169\u003c\/p\u003e \u003cp\u003e11.2 Common Methods for Assessing BBB Penetration 170\u003c\/p\u003e \u003cp\u003e11.3 Methods for Determination of Free Drug Concentration in the Brain 170\u003c\/p\u003e \u003cp\u003e11.4 Methods for BBB Permeability 172\u003c\/p\u003e \u003cp\u003e11.5 Methods for Pgp Efflux Transport 173\u003c\/p\u003e \u003cp\u003e11.6 Conclusions 174\u003c\/p\u003e \u003cp\u003eReferences 174\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Techniques for Determining Protein Binding in Drug Discovery and Development 177\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eTom Lloyd\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 177\u003c\/p\u003e \u003cp\u003e12.2 Overview 178\u003c\/p\u003e \u003cp\u003e12.3 Equilibrium Dialysis 179\u003c\/p\u003e \u003cp\u003e12.4 Ultracentrifugation 180\u003c\/p\u003e \u003cp\u003e12.5 Ultrafiltration 181\u003c\/p\u003e \u003cp\u003e12.6 Microdialysis 182\u003c\/p\u003e \u003cp\u003e12.7 Spectroscopy 182\u003c\/p\u003e \u003cp\u003e12.8 Chromatographic Methods 183\u003c\/p\u003e \u003cp\u003e12.9 Summary Discussion 183\u003c\/p\u003e \u003cp\u003eAcknowledgment 185\u003c\/p\u003e \u003cp\u003eReferences 185\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Reaction Phenotyping 189\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eChun Li and Nataraj Kalyanaraman\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 189\u003c\/p\u003e \u003cp\u003e13.2 Initial Considerations 190\u003c\/p\u003e \u003cp\u003e13.3 CYP Reaction Phenotyping 193\u003c\/p\u003e \u003cp\u003e13.4 Non-P450 Reaction Phenotyping 199\u003c\/p\u003e \u003cp\u003e13.5 UGT Conjugation Reaction Phenotyping 201\u003c\/p\u003e \u003cp\u003e13.6 Reaction Phenotyping for Other Conjugation Reactions 204\u003c\/p\u003e \u003cp\u003e13.7 Integration of Reaction Phenotyping and Prediction of DDI 205\u003c\/p\u003e \u003cp\u003e13.8 Conclusion 205\u003c\/p\u003e \u003cp\u003eReferences 206\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Fast and Reliable CYP Inhibition Assays 213\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eMing Yao, Hong Cai, and Mingshe Zhu\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 213\u003c\/p\u003e \u003cp\u003e14.2 CYP Inhibition Assays in Drug Discovery and Development 215\u003c\/p\u003e \u003cp\u003e14.3 HLM Reversible CYP Inhibition Assay Using Individual Substrates 217\u003c\/p\u003e \u003cp\u003e14.4 HLM RI Assay Using Multiple Substrates (Cocktail Assays) 222\u003c\/p\u003e \u003cp\u003e14.5 Time-Dependent CYP Inhibition Assay 226\u003c\/p\u003e \u003cp\u003e14.6 Summary and Future Directions 228\u003c\/p\u003e \u003cp\u003eReferences 230\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Tools and Strategies for the Assessment of Enzyme Induction in Drug Discovery and Development 233\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAdrian J. Fretland, Anshul Gupta, Peijuan Zhu, and Catherine L. Booth-Genthe\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction 233\u003c\/p\u003e \u003cp\u003e15.2 Understanding Induction at the Gene Regulation Level 233\u003c\/p\u003e \u003cp\u003e15.3 In silico Approaches 234\u003c\/p\u003e \u003cp\u003e15.4 In vitro Approaches 235\u003c\/p\u003e \u003cp\u003e15.5 In vitro Hepatocyte and Hepatocyte-Like Models 238\u003c\/p\u003e \u003cp\u003e15.6 Experimental Techniques for the Assessment of Induction in Cell-Based Assays 239\u003c\/p\u003e \u003cp\u003e15.7 Modeling and Simulation and Assessment of Risk 244\u003c\/p\u003e \u003cp\u003e15.8 Analysis of Induction in Preclinical Species 245\u003c\/p\u003e \u003cp\u003e15.9 Additional Considerations 245\u003c\/p\u003e \u003cp\u003e15.10 Conclusion 246\u003c\/p\u003e \u003cp\u003eReferences 246\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Animal Models for Studying Drug Metabolizing Enzymes and Transporters 253\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eKevin L. Salyers and Yang Xu\u003cbr\u003e\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 253\u003c\/p\u003e \u003cp\u003e16.2 Animal Models of DMEs 253\u003c\/p\u003e \u003cp\u003e16.3 Animal Models of Drug Transporters 263\u003c\/p\u003e \u003cp\u003e16.4 Conclusions and the Path Forward 270\u003c\/p\u003e \u003cp\u003eAcknowledgments 271\u003c\/p\u003e \u003cp\u003eReferences 271\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Milk Excretion and Placental Transfer Studies 277\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eMatthew Hoffmann and Adam Shilling\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction 277\u003c\/p\u003e \u003cp\u003e17.2 Compound Characteristics That Affect Placental Transfer and Lacteal Excretion 277\u003c\/p\u003e \u003cp\u003e17.3 Study Design 281\u003c\/p\u003e \u003cp\u003e17.4 Conclusions 289\u003c\/p\u003e \u003cp\u003eReferences 289\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 Human Bile Collection for ADME Studies 291\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eSuresh K. Balani, Lisa J. Christopher, and Donglu Zhang\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 291\u003c\/p\u003e \u003cp\u003e18.2 Physiology 291\u003c\/p\u003e \u003cp\u003e18.3 Utility of the Biliary Data 292\u003c\/p\u003e \u003cp\u003e18.4 Bile Collection Techniques 293\u003c\/p\u003e \u003cp\u003e18.5 Future Scope 297\u003c\/p\u003e \u003cp\u003eAcknowledgment 297\u003c\/p\u003e \u003cp\u003eReferences 297\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART C ANALYTICAL TECHNOLOGIES 299\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19 Current Technology and Limitation of LC-MS 301\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eCornelis E.C.A. Hop\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 301\u003c\/p\u003e \u003cp\u003e19.2 Sample Preparation 302\u003c\/p\u003e \u003cp\u003e19.3 Chromatography Separation 302\u003c\/p\u003e \u003cp\u003e19.4 Mass Spectrometric Analysis 304\u003c\/p\u003e \u003cp\u003e19.5 Ionization 304\u003c\/p\u003e \u003cp\u003e19.6 MS Mode versus MS\/MS or MSn Mode 305\u003c\/p\u003e \u003cp\u003e19.7 Mass Spectrometers: Single and Triple Quadrupole Mass Spectrometers 306\u003c\/p\u003e \u003cp\u003e19.8 Mass Spectrometers: Three-Dimensional and Linear Ion Traps 308\u003c\/p\u003e \u003cp\u003e19.9 Mass Spectrometers: Time-of-Flight Mass Spectrometers 308\u003c\/p\u003e \u003cp\u003e19.10 Mass Spectrometers: Fourier Transform and Orbitrap Mass Spectrometers 309\u003c\/p\u003e \u003cp\u003e19.11 Role of LC-MS in Quantitative in vitro ADME Studies 309\u003c\/p\u003e \u003cp\u003e19.12 Quantitative in vivo ADME Studies 311\u003c\/p\u003e \u003cp\u003e19.13 Metabolite Identification 312\u003c\/p\u003e \u003cp\u003e19.14 Tissue Imaging by MS 313\u003c\/p\u003e \u003cp\u003e19.15 Conclusions and Future Directions 313\u003c\/p\u003e \u003cp\u003eReferences 314\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20 Application of Accurate Mass Spectrometry for Metabolite Identification 317\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eZhoupeng Zhang and Kaushik Mitra\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction 317\u003c\/p\u003e \u003cp\u003e20.2 High-Resolution\/Accurate Mass Spectrometers 317\u003c\/p\u003e \u003cp\u003e20.3 Postacquisition Data Processing 318\u003c\/p\u003e \u003cp\u003e20.4 Utilities of High-Resolution\/Accurate Mass Spectrometry (HRMS) in Metabolite Identification 320\u003c\/p\u003e \u003cp\u003e20.5 Conclusion 328\u003c\/p\u003e \u003cp\u003eReferences 329\u003c\/p\u003e \u003cp\u003e\u003cb\u003e21 Applications of Accelerator Mass Spectrometry (AMS) 331\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eXiaomin Wang, Voon Ong, and Mark Seymour\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e21.1 Introduction 331\u003c\/p\u003e \u003cp\u003e21.2 Bioanalytical Methodology 332\u003c\/p\u003e \u003cp\u003eReferences 337\u003c\/p\u003e \u003cp\u003e\u003cb\u003e22 Radioactivity Profiling 339\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eWing Wah Lam, Jose Silva, and Heng-Keang Lim\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e22.1 Introduction 339\u003c\/p\u003e \u003cp\u003e22.2 Radioactivity Detection Methods 340\u003c\/p\u003e \u003cp\u003e22.3 AMS 346\u003c\/p\u003e \u003cp\u003e22.4 Intracavity Optogalvanic Spectroscopy 349\u003c\/p\u003e \u003cp\u003e22.5 Summary 349\u003c\/p\u003e \u003cp\u003eAcknowledgments 349\u003c\/p\u003e \u003cp\u003eReferences 349\u003c\/p\u003e \u003cp\u003e\u003cb\u003e23 A Robust Methodology for Rapid Structure Determination of Microgram-Level Drug Metabolites by NMR Spectroscopy 353\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eKim A. Johnson, Stella Huang, and Yue-Zhong Shu\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e23.1 Introduction 353\u003c\/p\u003e \u003cp\u003e23.2 Methods 354\u003c\/p\u003e \u003cp\u003e23.3 Trazodone and Its Metabolism 355\u003c\/p\u003e \u003cp\u003e23.4 Trazodone Metabolite Generation and NMR Sample Preparation 356\u003c\/p\u003e \u003cp\u003e23.5 Metabolite Characterization 356\u003c\/p\u003e \u003cp\u003e23.6 Comparison with Flow Probe and LC-NMR Methods 361\u003c\/p\u003e \u003cp\u003e23.7 Metabolite Quantification by NMR 361\u003c\/p\u003e \u003cp\u003e23.8 Conclusion 361\u003c\/p\u003e \u003cp\u003eReferences 362\u003c\/p\u003e \u003cp\u003e\u003cb\u003e24 Supercritical Fluid Chromatography 363\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eJun Dai, Yingru Zhang, David B. Wang-Iverson, and Adrienne A. Tymiak\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e24.1 Introduction 363\u003c\/p\u003e \u003cp\u003e24.2 Background 363\u003c\/p\u003e \u003cp\u003e24.3 SFC Instrumentation and General Considerations 364\u003c\/p\u003e \u003cp\u003e24.4 SFC in Drug Discovery and Development 369\u003c\/p\u003e \u003cp\u003e24.5 Future Perspective 375\u003c\/p\u003e \u003cp\u003eReferences 376\u003c\/p\u003e \u003cp\u003e\u003cb\u003e25 Chromatographic Separation Methods 381\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eWenying Jian, Richard W. Edom, Zhongping (John) Lin, and Naidong Weng\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e25.1 Introduction 381\u003c\/p\u003e \u003cp\u003e25.2 LC Separation Techniques 383\u003c\/p\u003e \u003cp\u003e25.3 Sample Preparation Techniques 388\u003c\/p\u003e \u003cp\u003e25.4 High-Speed LC-MS Analysis 390\u003c\/p\u003e \u003cp\u003e25.5 Orthogonal Separation 394\u003c\/p\u003e \u003cp\u003e25.6 Conclusions and Perspectives 395\u003c\/p\u003e \u003cp\u003eReferences 396\u003c\/p\u003e \u003cp\u003e\u003cb\u003e26 Mass Spectrometric Imaging for Drug Distribution in Tissues 401\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eDaniel P. Magparangalan, Timothy J. Garrett, Dieter M. Drexler, and Richard A. Yost\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e26.1 Introduction 401\u003c\/p\u003e \u003cp\u003e26.2 MSI Instrumentation 403\u003c\/p\u003e \u003cp\u003e26.3 MSI Workfl ow 406\u003c\/p\u003e \u003cp\u003e26.4 Applications of MSI for in situ ADMET Tissue Studies 408\u003c\/p\u003e \u003cp\u003e26.5 Conclusions 413\u003c\/p\u003e \u003cp\u003eReferences 414\u003c\/p\u003e \u003cp\u003e\u003cb\u003e27 Applications of Quantitative Whole-Body Autoradiography (QWBA) in Drug Discovery and Development 419\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eLifei Wang, Haizheng Hong, and Donglu Zhang\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e27.1 Introduction 419\u003c\/p\u003e \u003cp\u003e27.2 Equipment and Materials 419\u003c\/p\u003e \u003cp\u003e27.3 Study Designs 420\u003c\/p\u003e \u003cp\u003e27.4 QWBA Experimental Procedures 420\u003c\/p\u003e \u003cp\u003e27.5 Applications of QWBA 421\u003c\/p\u003e \u003cp\u003e27.6 Limitations of QWBA 432\u003c\/p\u003e \u003cp\u003eReferences 433\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePART D NEW AND RELATED TECHNOLOGIES 435\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e28 Genetically Modified Mouse Models in ADME Studies 437\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eXi-Ling Jiang and Ai-Ming Yu\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e28.1 Introduction 437\u003c\/p\u003e \u003cp\u003e28.2 Drug Metabolizing Enzyme Genetically Modified Mouse Models 438\u003c\/p\u003e \u003cp\u003e28.3 Drug Transporter Genetically Modifi ed Mouse Models 442\u003c\/p\u003e \u003cp\u003e28.4 Xenobiotic Receptor Genetically Modified Mouse Models 446\u003c\/p\u003e \u003cp\u003e28.5 Conclusions 448\u003c\/p\u003e \u003cp\u003eReferences 448\u003c\/p\u003e \u003cp\u003e\u003cb\u003e29 Pluripotent Stem Cell Models in Human Drug Development 455\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eDavid C. Hay\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e29.1 Introduction 455\u003c\/p\u003e \u003cp\u003e29.2 Human Drug Metabolism and Compound Attrition 455\u003c\/p\u003e \u003cp\u003e29.3 Human Hepatocyte Supply 456\u003c\/p\u003e \u003cp\u003e29.4 hESCS 456\u003c\/p\u003e \u003cp\u003e29.5 hESC HLC Differentiation 456\u003c\/p\u003e \u003cp\u003e29.6 iPSCS 456\u003c\/p\u003e \u003cp\u003e29.7 CYP P450 Expression in Stem Cell-Derived HLCs 457\u003c\/p\u003e \u003cp\u003e29.8 Tissue Culture Microenvironment 457\u003c\/p\u003e \u003cp\u003e29.9 Culture Defi nition for Deriving HLCS from Stem Cells 457\u003c\/p\u003e \u003cp\u003e29.10 Conclusion 457\u003c\/p\u003e \u003cp\u003eReferences 458\u003c\/p\u003e \u003cp\u003e\u003cb\u003e30 Radiosynthesis for ADME Studies 461\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eBrad D. Maxwell and Charles S. Elmore\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e30.1 Background and General Requirements 461\u003c\/p\u003e \u003cp\u003e30.2 Radiosynthesis Strategies and Goals 463\u003c\/p\u003e \u003cp\u003e30.3 Preparation and Synthesis 467\u003c\/p\u003e \u003cp\u003e30.4 Analysis and Product Release 469\u003c\/p\u003e \u003cp\u003e30.5 Documentation 471\u003c\/p\u003e \u003cp\u003e30.6 Summary 471\u003c\/p\u003e \u003cp\u003eReferences 471\u003c\/p\u003e \u003cp\u003e\u003cb\u003e31 Formulation Development for Preclinical in vivo Studies 473\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eYuan-Hon Kiang, Darren L. Reid, and Janan Jona\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e31.1 Introduction 473\u003c\/p\u003e \u003cp\u003e31.2 Formulation Consideration for the Intravenous Route 473\u003c\/p\u003e \u003cp\u003e31.3 Formulation Consideration for the Oral, Subcutaneous, and Intraperitoneal Routes 474\u003c\/p\u003e \u003cp\u003e31.4 Special Consideration for the Intraperitoneal Route 475\u003c\/p\u003e \u003cp\u003e31.5 Solubility Enhancement 475\u003c\/p\u003e \u003cp\u003e31.6 pH Manipulation 476\u003c\/p\u003e \u003cp\u003e31.7 Cosolvents Utilization 477\u003c\/p\u003e \u003cp\u003e31.8 Complexation 479\u003c\/p\u003e \u003cp\u003e31.9 Amorphous Form Approach 479\u003c\/p\u003e \u003cp\u003e31.10 Improving the Dissolution Rate 479\u003c\/p\u003e \u003cp\u003e31.11 Formulation for Toxicology Studies 479\u003c\/p\u003e \u003cp\u003e31.12 Timing and Assessment of Physicochemical Properties 480\u003c\/p\u003e \u003cp\u003e31.13 Critical Issues with Solubility and Stability 481\u003c\/p\u003e \u003cp\u003e31.14 General and Quick Approach for Formulation Identification at the Early Discovery Stages 482\u003c\/p\u003e \u003cp\u003eReferences 482\u003c\/p\u003e \u003cp\u003e\u003cb\u003e32 In vitro Testing of Proarrhythmic Toxicity 485\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eHaoyu Zeng and Jiesheng Kang\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e32.1 Objectives, Rationale, and Regulatory Compliance 485\u003c\/p\u003e \u003cp\u003e32.2 Study System and Design 486\u003c\/p\u003e \u003cp\u003e32.3 Good Laboratory Practice (GLP)-hERG Study 489\u003c\/p\u003e \u003cp\u003e32.4 Medium-Throughput Assays Using PatchXpress as a Case Study 490\u003c\/p\u003e \u003cp\u003e32.5 Nonfunctional and Functional Assays for hERG Traffi cking 491\u003c\/p\u003e \u003cp\u003e32.6 Conclusions and the Path Forward 491\u003c\/p\u003e \u003cp\u003eReferences 492\u003c\/p\u003e \u003cp\u003e\u003cb\u003e33 Target Engagement for PK\/PD Modeling and Translational Imaging Biomarkers 493\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eVanessa N. Barth, Elizabeth M. Joshi, and Matthew D. Silva\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e33.1 Introduction 493\u003c\/p\u003e \u003cp\u003e33.2 Application of LC-MS\/MS to Assess Target Engagement 494\u003c\/p\u003e \u003cp\u003e33.3 LC-MS\/MS-Based RO Study Designs and Their Calculations 494\u003c\/p\u003e \u003cp\u003e33.4 Leveraging Target Engagement Data for Drug Discovery from an Absorption, Distribution, Metabolism, and Excretion (ADME) Perspective 497\u003c\/p\u003e \u003cp\u003e33.5 Application of LC-MS\/MS to Discovery Novel Tracers 502\u003c\/p\u003e \u003cp\u003e33.6 Noninvasive Translational Imaging 503\u003c\/p\u003e \u003cp\u003e33.7 Conclusions and the Path Forward 507\u003c\/p\u003e \u003cp\u003eReferences 508\u003c\/p\u003e \u003cp\u003e\u003cb\u003e34 Applications of iRNA Technologies in Drug Transporters and Drug Metabolizing Enzymes 513\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eMingxiang Liao and Cindy Q. Xia\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e34.1 Introduction 513\u003c\/p\u003e \u003cp\u003e34.2 Experimental Designs 514\u003c\/p\u003e \u003cp\u003e34.3 Applications of RNAi in Drug Metabolizing Enzymes and Transporters 527\u003c\/p\u003e \u003cp\u003e34.4 Conclusions 538\u003c\/p\u003e \u003cp\u003eAcknowledgment 539\u003c\/p\u003e \u003cp\u003eReferences 539\u003c\/p\u003e \u003cp\u003e\u003cb\u003eAppendix Drug Metabolizing Enzymes and Biotransformation Reactions 545\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eNatalia Penner, Caroline Woodward, and Chandra Prakash\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eA.1 Introduction 545\u003c\/p\u003e \u003cp\u003eA.2 Oxidative Enzymes 547\u003c\/p\u003e \u003cp\u003eA.3 Reductive Enzymes 550\u003c\/p\u003e \u003cp\u003eA.4 Hydrolytic Enzymes 551\u003c\/p\u003e \u003cp\u003eA.5 Conjugative (Phase II) DMEs 553\u003c\/p\u003e \u003cp\u003eA.6 Factors Affecting DME Activities 555\u003c\/p\u003e \u003cp\u003eA.7 Biotransformation Reactions 557\u003c\/p\u003e \u003cp\u003eA.8 Summary 561\u003c\/p\u003e \u003cp\u003eAcknowledgment 562\u003c\/p\u003e \u003cp\u003eReferences 562\u003c\/p\u003e \u003cp\u003eIndex 567\u003c\/p\u003e  \u003cp\u003e“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.”  (\u003ci\u003eBritish Toxicology Society\u003c\/i\u003e, 1 July 2013)\u003c\/p\u003e \u003cp\u003e \u003c\/p\u003e \u003cp\u003e\u003cb\u003eDonglu Zhang\u003c\/b\u003e, 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.\u003c\/p\u003e \u003cp\u003e\u003cb\u003eSekhar Surapaneni\u003c\/b\u003e, 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.\u003c\/p\u003e  \u003cp\u003eA comprehensive guide to cutting-edge tools in ADME research\u003c\/p\u003e \u003cp\u003eThe 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).\u003c\/p\u003e \u003cp\u003eADME-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:\u003c\/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eA thorough examination of current tools, covering both electronic\/mechanical technologies and biologically based ones\u003c\/p\u003e \u003c\/li\u003e \u003cli\u003e \u003cp\u003eCoverage of applications for each technology, including key parameters, optimal conditions for intended results, protocols, and case studies\u003c\/p\u003e \u003c\/li\u003e \u003cli\u003e \u003cp\u003eDetailed discussion of emerging tools and techniques, from stem cells and genetically modified animal models to imaging technologies\u003c\/p\u003e \u003c\/li\u003e \u003cli\u003e \u003cp\u003eNumerous figures and diagrams throughout the text\u003c\/p\u003e \u003c\/li\u003e \u003c\/ul\u003e \u003cp\u003eScientists 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.\u003c\/p\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47988661715173,"sku":"NP9780470542781","price":215.95,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9780470542781.jpg?v=1761781163","url":"https:\/\/k12savings.com\/products\/adme-enabling-technologies-in-drug-design-and-development-isbn-9780470542781","provider":"K12savings","version":"1.0","type":"link"}