{"product_id":"drug-bioavailability-estimation-of-solubility-permeability-absorption-and-bioavailability-9783527320516","title":"Drug Bioavailability: Estimation of Solubility, Permeability, Absorption and Bioavailability","description":"\u003cb\u003eBook Synopsis\u003c\/b\u003e\u003cbr\u003e\u003cb\u003eDrug Bioavailability\u003c\/b\u003e \u003cp\u003eIn order to reach its intended site of action, the drug molecules in every pill that we swallow must first be absorbed, transported via the bloodstream and evade various mechanisms that eliminate drugs from the body. Those drug properties that determine, for example, its stability in the gut or its ease of uptake into the bloodstream, are therefore of central importance in drug development. In fact, many potentially useful drugs fail because of insufficient availability at the biological target site.  \u003c\/p\u003e\u003cp\u003eThis second edition of the gold standard for industrial research is thoroughly revised in line with current trends in the field, with all contributions extensively updated or rewritten. No other publication offers the same level of treatment on this crucial topic.  \u003c\/p\u003e\u003cp\u003eIn 22 chapters readers can benefit from the key working knowledge of today’s leading pharmaceutical companies, including Pfizer, AstraZeneca, and Roche. Drug developers from industry and academia present all the factors governing drug bioavailability, complete with practical examples and real-life data.  \u003c\/p\u003e\u003cp\u003ePart I focuses on solubility and gastrointestinal absorption, while the second discusses in vitro and in vivo measurements of physicochemical properties, such as membrane permeability and solubility. Part III is devoted to metabolism and excretory mechanisms. The much revised and expanded Part IV surveys current in silico approaches to predict drug properties needed to estimate the bioavailability of any new drug candidate. The final part shows new drug development approaches as well as delivery strategies.  \u003c\/p\u003e\u003cp\u003eIndispensable for all those working in the pharmaceutical industry, pharmaceutical and medicinal chemists, and toxicologists.\u003c\/p\u003e\u003cbr\u003e\u003cbr\u003e\u003cb\u003eTrade Review\u003c\/b\u003e\u003cbr\u003e\"The book covers a wide range of topics and, as such, it will serve as a valuable reference for pharmaceutical scientists, toxicologists, academicians, and the graduate students.\" (\u003ci\u003eDoody's\u003c\/i\u003e, May 2009)\u003cbr\u003e\u003cbr\u003e\u003cb\u003eTable of Contents\u003c\/b\u003e\u003cbr\u003e\u003cp\u003eList of Contributors XIX\u003c\/p\u003e \u003cp\u003ePreface XXIII\u003c\/p\u003e \u003cp\u003eA Personal Foreword XXV\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 Introduction: The Why and How of Drug Bioavailability Research 1\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eHan van de Waterbeemd and Bernard Testa\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Defining Bioavailability 1\u003c\/p\u003e \u003cp\u003e1.1.1 The Biological Context 1\u003c\/p\u003e \u003cp\u003e1.1.2 A Pharmacokinetic Overview 3\u003c\/p\u003e \u003cp\u003e1.1.3 Specific Issues 3\u003c\/p\u003e \u003cp\u003e1.2 Presentation and Layout of the Book 4\u003c\/p\u003e \u003cp\u003eReferences 6\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart One Physicochemical Aspects of Drug Dissolution and Solubility 7\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 Aqueous Solubility in Drug Discovery Chemistry, DMPK, and Biological Assays 9\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eNicola Colclough, Linette Ruston, and Kin Tam\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Introduction 10\u003c\/p\u003e \u003cp\u003e2.1.1 Definition of Aqueous Solubility 11\u003c\/p\u003e \u003cp\u003e2.1.2 Aqueous Solubility in Different Phases of Drug Discovery 12\u003c\/p\u003e \u003cp\u003e2.2 Aqueous Solubility in Hit Identification 12\u003c\/p\u003e \u003cp\u003e2.2.1 Aqueous Solubility from DMSO Solutions 13\u003c\/p\u003e \u003cp\u003e2.2.1.1 Turbidimetric Methods 14\u003c\/p\u003e \u003cp\u003e2.2.1.2 UV Absorption Methods 15\u003c\/p\u003e \u003cp\u003e2.2.1.3 Alternative Detection Methodology 17\u003c\/p\u003e \u003cp\u003e2.2.1.4 Application of DMSO-Based Solubility Assays 18\u003c\/p\u003e \u003cp\u003e2.3 Aqueous Solubility in Lead Identification and Lead Optimization 18\u003c\/p\u003e \u003cp\u003e2.3.1 Dried-Down Solution Methods 20\u003c\/p\u003e \u003cp\u003e2.3.2 Solubility from Solid 21\u003c\/p\u003e \u003cp\u003e2.3.3 Thermodynamic Solubility Assays with Solid-State Characterization 22\u003c\/p\u003e \u003cp\u003e2.3.4 Solubility by Potentiometry 24\u003c\/p\u003e \u003cp\u003e2.3.5 Application of Thermodynamic Solubility Data in LI and LO 26\u003c\/p\u003e \u003cp\u003e2.4 Conclusions 28\u003c\/p\u003e \u003cp\u003eReferences 28\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Gastrointestinal Dissolution and Absorption of Class II Drugs 33\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eArik S. Dahan and Gordon L. Amidon\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Introduction 33\u003c\/p\u003e \u003cp\u003e3.2 Drug Absorption and the BCS 34\u003c\/p\u003e \u003cp\u003e3.3 Class II Drugs 36\u003c\/p\u003e \u003cp\u003e3.4 GI Physiological Variables Affecting Class II Drug Dissolution 38\u003c\/p\u003e \u003cp\u003e3.4.1 Bile Salts 38\u003c\/p\u003e \u003cp\u003e3.4.2 GI pH 39\u003c\/p\u003e \u003cp\u003e3.4.3 GI Transit 39\u003c\/p\u003e \u003cp\u003e3.4.4 Drug Particle Size 40\u003c\/p\u003e \u003cp\u003e3.4.5 Volume Available for Dissolution 41\u003c\/p\u003e \u003cp\u003e3.5 \u003ci\u003eIn Vitro\u003c\/i\u003e Dissolution Tests for Class II Drugs 41\u003c\/p\u003e \u003cp\u003e3.5.1 Biorelevant Media 41\u003c\/p\u003e \u003cp\u003e3.5.2 Dynamic Lipolysis Model 42\u003c\/p\u003e \u003cp\u003e3.6 BCS-Based FDA Guidelines: Implications for Class II Drugs 43\u003c\/p\u003e \u003cp\u003e3.6.1 Potential of Redefining BCS Solubility Class Boundary 43\u003c\/p\u003e \u003cp\u003e3.6.2 Biowaiver Extension Potential for Class II Drugs 44\u003c\/p\u003e \u003cp\u003e3.7 Conclusions 45\u003c\/p\u003e \u003cp\u003eReferences 45\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 In Silico Prediction of Solubility 53\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAndrew M. Davis and Pierre Bruneau\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 54\u003c\/p\u003e \u003cp\u003e4.2 What Solubility Measures to Model? 54\u003c\/p\u003e \u003cp\u003e4.3 Is the Data Set Suitable for Modeling? 56\u003c\/p\u003e \u003cp\u003e4.4 Descriptors and Modeling Methods for Developing Solubility Models 58\u003c\/p\u003e \u003cp\u003e4.5 Comparing Literature Solubility Models 59\u003c\/p\u003e \u003cp\u003e4.6 What Is the Influence of the Domain of Applicability? 63\u003c\/p\u003e \u003cp\u003e4.7 Can We Tell when Good Predictions Are Made? 65\u003c\/p\u003e \u003cp\u003e4.8 Conclusions 65\u003c\/p\u003e \u003cp\u003eReferences 66\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart Two Physicochemical and Biological Studies of Membrane Permeability and Oral Absorption 69\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Physicochemical Approaches to Drug Absorption 71\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eHan van de Waterbeemd\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 73\u003c\/p\u003e \u003cp\u003e5.2 Physicochemical Properties and Pharmacokinetics 74\u003c\/p\u003e \u003cp\u003e5.2.1 DMPK 74\u003c\/p\u003e \u003cp\u003e5.2.2 Lipophilicity, Permeability, and Absorption 74\u003c\/p\u003e \u003cp\u003e5.2.3 Estimation of Volume of Distribution from Physical Chemistry 76\u003c\/p\u003e \u003cp\u003e5.2.4 Plasma Protein Binding and Physicochemical Properties 76\u003c\/p\u003e \u003cp\u003e5.3 Dissolution and Solubility 76\u003c\/p\u003e \u003cp\u003e5.3.1 Calculated Solubility 78\u003c\/p\u003e \u003cp\u003e5.4 Ionization (pK\u003csub\u003ea\u003c\/sub\u003e) 78\u003c\/p\u003e \u003cp\u003e5.4.1 Calculated pK\u003csub\u003ea\u003c\/sub\u003e 79\u003c\/p\u003e \u003cp\u003e5.5 Molecular Size and Shape 79\u003c\/p\u003e \u003cp\u003e5.5.1 Calculated Size Descriptors 79\u003c\/p\u003e \u003cp\u003e5.6 Hydrogen Bonding 80\u003c\/p\u003e \u003cp\u003e5.6.1 Calculated Hydrogen-Bonding Descriptors 80\u003c\/p\u003e \u003cp\u003e5.7 Lipophilicity 81\u003c\/p\u003e \u003cp\u003e5.7.1 log \u003ci\u003eP\u003c\/i\u003e and log \u003ci\u003eD \u003c\/i\u003e81\u003c\/p\u003e \u003cp\u003e5.7.2 Calculated log \u003ci\u003eP\u003c\/i\u003e and log \u003ci\u003eD\u003c\/i\u003e 83\u003c\/p\u003e \u003cp\u003e5.8 Permeability 84\u003c\/p\u003e \u003cp\u003e5.8.1 Artificial Membranes and PAMPA 84\u003c\/p\u003e \u003cp\u003e5.8.1.1 In Silico PAMPA 85\u003c\/p\u003e \u003cp\u003e5.8.2 IAM, ILC, MEKC, and BMC 85\u003c\/p\u003e \u003cp\u003e5.8.3 Liposome Partitioning 86\u003c\/p\u003e \u003cp\u003e5.8.4 Biosensors 86\u003c\/p\u003e \u003cp\u003e5.9 Amphiphilicity 86\u003c\/p\u003e \u003cp\u003e5.10 Drug-Like Properties 87\u003c\/p\u003e \u003cp\u003e5.11 Computation Versus Measurement of Physicochemical Properties 88\u003c\/p\u003e \u003cp\u003e5.11.1 QSAR Modeling 88\u003c\/p\u003e \u003cp\u003e5.11.2 \u003ci\u003eIn Combo\u003c\/i\u003e: Using the Best of Two Worlds 89\u003c\/p\u003e \u003cp\u003e5.12 Outlook 89\u003c\/p\u003e \u003cp\u003eReferences 89\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 High-Throughput Measurement of Physicochemical Properties 101\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eBarbara P. Mason\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 102\u003c\/p\u003e \u003cp\u003e6.2 Positioning of Physicochemical Screening in Drug Discovery 102\u003c\/p\u003e \u003cp\u003e6.3 ‘‘Fit for Purpose’’ Versus ‘‘Gold Standard’’ 103\u003c\/p\u003e \u003cp\u003e6.4 Solubility 104\u003c\/p\u003e \u003cp\u003e6.4.1 ‘‘Thermodynamic’’ Versus ‘‘Kinetic’’ 104\u003c\/p\u003e \u003cp\u003e6.4.2 Methods of Measuring High-Throughput Solubility 106\u003c\/p\u003e \u003cp\u003e6.4.3 Supernatant Concentration 106\u003c\/p\u003e \u003cp\u003e6.4.4 Measuring Solubility Across a pH Range 107\u003c\/p\u003e \u003cp\u003e6.4.5 Supernatant Concentration Methods from Solid Material 109\u003c\/p\u003e \u003cp\u003e6.4.6 Precipitate Detection 109\u003c\/p\u003e \u003cp\u003e6.4.7 Other Methods of Measuring Solubility 110\u003c\/p\u003e \u003cp\u003e6.5 Dissociation Constants, pKa 110\u003c\/p\u003e \u003cp\u003e6.5.1 Measuring pKa 111\u003c\/p\u003e \u003cp\u003e6.5.2 pK\u003csub\u003ea\u003c\/sub\u003e Measurements in Cosolvent Mixtures 112\u003c\/p\u003e \u003cp\u003e6.5.3 pK\u003csub\u003ea\u003c\/sub\u003e Measurements based on Separation 113\u003c\/p\u003e \u003cp\u003e6.6 Lipophilicity 115\u003c\/p\u003e \u003cp\u003e6.6.1 log P Versus log DpH 115\u003c\/p\u003e \u003cp\u003e6.6.2 Measuring Lipophilicity 116\u003c\/p\u003e \u003cp\u003e6.6.3 High-Throughput log D\u003csub\u003e7.4 \u003c\/sub\u003eMeasurements 117\u003c\/p\u003e \u003cp\u003e6.6.4 High-Throughput log D\u003csub\u003e7.4\u003c\/sub\u003e Versus Shake-Flask log D\u003csub\u003e7.4\u003c\/sub\u003e 117\u003c\/p\u003e \u003cp\u003e6.6.5 Alternative Methods for Determining High-Throughput log D\u003csub\u003epH\u003c\/sub\u003e 118\u003c\/p\u003e \u003cp\u003e6.7 Permeability 119\u003c\/p\u003e \u003cp\u003e6.7.1 Permeability and Lipophilicity 121\u003c\/p\u003e \u003cp\u003e6.7.2 Cell-Based Assays 121\u003c\/p\u003e \u003cp\u003e6.7.3 Noncell-Based Assays: Chromatographic Methods 122\u003c\/p\u003e \u003cp\u003e6.7.4 Noncell-Based Assays: Parallel Artificial Membrane Permeability Assay 122\u003c\/p\u003e \u003cp\u003e6.7.4.1 Membrane Composition 123\u003c\/p\u003e \u003cp\u003e6.7.4.2 Suggestions for PAMPA 123\u003c\/p\u003e \u003cp\u003e6.7.4.3 Considerations in the Calculation of Permeability from PAMPA Data 124\u003c\/p\u003e \u003cp\u003e6.7.5 Sink Conditions 125\u003c\/p\u003e \u003cp\u003e6.7.6 Unstirred Water Layer 126\u003c\/p\u003e \u003cp\u003e6.7.7 Surface Properties for the Determination of Permeability 126\u003c\/p\u003e \u003cp\u003e6.8 Data Interpretation, Presentation, and Storage 126\u003c\/p\u003e \u003cp\u003e6.9 Conclusions 127\u003c\/p\u003e \u003cp\u003eReferences 127\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 An Overview of Caco-2 and Alternatives for Prediction of Intestinal Drug Transport and Absorption 133\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAnna-Lena Ungell and Per Artursson\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 134\u003c\/p\u003e \u003cp\u003e7.2 Cell Cultures for Assessment of Intestinal Permeability 134\u003c\/p\u003e \u003cp\u003e7.2.1 Caco-2 135\u003c\/p\u003e \u003cp\u003e7.2.2 MDCK Cells 136\u003c\/p\u003e \u003cp\u003e7.2.3 2\/4\/A1 Cells 137\u003c\/p\u003e \u003cp\u003e7.2.4 Other Cell Lines 139\u003c\/p\u003e \u003cp\u003e7.3 Correlation to Fraction of Oral Dose Absorbed 140\u003c\/p\u003e \u003cp\u003e7.4 Cell Culture and Transport Experiments 141\u003c\/p\u003e \u003cp\u003e7.4.1 Quality Control and Standardization 143\u003c\/p\u003e \u003cp\u003e7.4.2 Optimizing Experimental Conditions: pH 144\u003c\/p\u003e \u003cp\u003e7.4.3 Optimizing Experimental Conditions: Concentration Dependence 144\u003c\/p\u003e \u003cp\u003e7.4.4 Optimizing Experimental Conditions: Solubility and BSA 145\u003c\/p\u003e \u003cp\u003e7.5 Active Transport Studies in Caco-2 Cells 145\u003c\/p\u003e \u003cp\u003e7.6 Metabolism Studies using Caco-2 Cells 146\u003c\/p\u003e \u003cp\u003e7.7 Conclusions 147\u003c\/p\u003e \u003cp\u003eReferences 148\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Use of Animals for the Determination of Absorption and Bioavailability 161\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eChris Logan\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 162\u003c\/p\u003e \u003cp\u003e8.1.1 ADME\/PK in Drug Discovery 162\u003c\/p\u003e \u003cp\u003e8.1.2 The Need for Prediction 163\u003c\/p\u003e \u003cp\u003e8.2 Consideration of Absorption and Bioavailability 163\u003c\/p\u003e \u003cp\u003e8.3 Choice of Animal Species 167\u003c\/p\u003e \u003cp\u003e8.4 Methods 168\u003c\/p\u003e \u003cp\u003e8.4.1 Radiolabels 169\u003c\/p\u003e \u003cp\u003e8.4.2 \u003ci\u003eEx Vivo\u003c\/i\u003e Methods for Absorption 169\u003c\/p\u003e \u003cp\u003e8.4.2.1 Static Method 169\u003c\/p\u003e \u003cp\u003e8.4.2.2 Perfusion Methods 170\u003c\/p\u003e \u003cp\u003e8.4.3 \u003ci\u003eIn Vivo\u003c\/i\u003e Methods 170\u003c\/p\u003e \u003cp\u003e8.5 \u003ci\u003eIn Vivo\u003c\/i\u003e Methods for Determining Bioavailability 171\u003c\/p\u003e \u003cp\u003e8.5.1 Cassette Dosing 171\u003c\/p\u003e \u003cp\u003e8.5.2 Semisimultaneous Dosing 172\u003c\/p\u003e \u003cp\u003e8.5.3 Hepatic Portal Vein Cannulation 173\u003c\/p\u003e \u003cp\u003e8.6 Inhalation 173\u003c\/p\u003e \u003cp\u003e8.7 Relevance of Animal Models 174\u003c\/p\u003e \u003cp\u003e8.7.1 Models for Prediction of Absorption 174\u003c\/p\u003e \u003cp\u003e8.7.2 Models for Prediction of Volume 175\u003c\/p\u003e \u003cp\u003e8.8 Prediction of Dose in Man 176\u003c\/p\u003e \u003cp\u003e8.8.1 Allometry 176\u003c\/p\u003e \u003cp\u003e8.8.2 Physiologically Based Pharmacokinetics 176\u003c\/p\u003e \u003cp\u003e8.8.3 Prediction of Human Dose 177\u003c\/p\u003e \u003cp\u003e8.9 Conclusions 179\u003c\/p\u003e \u003cp\u003eReferences 179\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 In Vivo Permeability Studies in the Gastrointestinal Tract of Humans 185\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eNiclas Petri and Hans Lennernäs\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction 185\u003c\/p\u003e \u003cp\u003e9.2 Definitions of Intestinal Absorption, Presystemic Metabolism, and Absolute Bioavailability 188\u003c\/p\u003e \u003cp\u003e9.3 Methodological Aspects of In Vitro Intestinal Perfusion Techniques 190\u003c\/p\u003e \u003cp\u003e9.4 Paracellular Passive Diffusion 193\u003c\/p\u003e \u003cp\u003e9.5 Transcellular Passive Diffusion 196\u003c\/p\u003e \u003cp\u003e9.6 Carrier-Mediated Intestinal Absorption 199\u003c\/p\u003e \u003cp\u003e9.7 Jejunal Transport and Metabolism 202\u003c\/p\u003e \u003cp\u003e9.8 Regional Differences in Transport and Metabolism of Drugs 208\u003c\/p\u003e \u003cp\u003e9.9 Conclusions 209\u003c\/p\u003e \u003cp\u003eReferences 210\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart Three Role of Transporters and Metabolism in Oral Absorption 221\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Transporters in the Gastrointestinal Tract 223\u003cbr\u003e\u003c\/b\u003e\u003ci\u003ePascale Anderle and Carsten U. Nielsen\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction 223\u003c\/p\u003e \u003cp\u003e10.2 Active Transport Along the Intestine and Influence on Drug Absorption 228\u003c\/p\u003e \u003cp\u003e10.2.1 Peptide Transporters 232\u003c\/p\u003e \u003cp\u003e10.2.2 Nucleoside Transporters 233\u003c\/p\u003e \u003cp\u003e10.2.3 Amino Acid Transporters 234\u003c\/p\u003e \u003cp\u003e10.2.4 Monosaccharide Transporters 234\u003c\/p\u003e \u003cp\u003e10.2.5 Organic Cation Transporters 235\u003c\/p\u003e \u003cp\u003e10.2.6 Organic Anion Transporters 235\u003c\/p\u003e \u003cp\u003e10.2.7 Monocarboxylate Transporters 235\u003c\/p\u003e \u003cp\u003e10.2.8 ABC Transporters 235\u003c\/p\u003e \u003cp\u003e10.2.9 Bile Acid Transporters 237\u003c\/p\u003e \u003cp\u003e10.3 Transporters and Genomics 237\u003c\/p\u003e \u003cp\u003e10.3.1 Introduction to Genomics Technologies 237\u003c\/p\u003e \u003cp\u003e10.3.2 Gene Expression Profiling Along the Intestine and in Caco-2 Cells 238\u003c\/p\u003e \u003cp\u003e10.3.2.1 Profiling of the Intestinal Mucosa 238\u003c\/p\u003e \u003cp\u003e10.3.2.2 Profiling of Caco-2 Cells 240\u003c\/p\u003e \u003cp\u003e10.3.3 Intestinal Transporters and the Influence of Genotypes 242\u003c\/p\u003e \u003cp\u003e10.4 Structural Requirements for Targeting Absorptive Intestinal Transporters 245\u003c\/p\u003e \u003cp\u003e10.4.1 Strategies for Increasing Drug Absorption Targeting Transporters 245\u003c\/p\u003e \u003cp\u003e10.4.2 Changing the Substrate: SAR Established for PEPT1 247\u003c\/p\u003e \u003cp\u003e10.4.3 Methods for Investigating Affinity and Translocation 248\u003c\/p\u003e \u003cp\u003e10.4.4 Quantitative Structure–Activity Relations for Binding of Drug to Transporters 249\u003c\/p\u003e \u003cp\u003e10.5 Transporters and Diseased States of the Intestine 251\u003c\/p\u003e \u003cp\u003e10.5.1 Intestinal Diseases 251\u003c\/p\u003e \u003cp\u003e10.5.2 Basic Mechanisms in Cancer and Specifically in Colon Carcinogenesis 252\u003c\/p\u003e \u003cp\u003e10.5.2.1 Basic Mechanisms 252\u003c\/p\u003e \u003cp\u003e10.5.2.2 Colon Cancer 253\u003c\/p\u003e \u003cp\u003e10.5.3 Transporters and Colon Cancer 253\u003c\/p\u003e \u003cp\u003e10.5.3.1 Transporters as Tumor Suppressor Genes 255\u003c\/p\u003e \u003cp\u003e10.5.3.2 Role of Transporters in the Tumor–Stroma Interaction 255\u003c\/p\u003e \u003cp\u003e10.5.3.3 Role of Transporters in Intestinal Stem Cells 258\u003c\/p\u003e \u003cp\u003e10.5.4 Role of PEPT1 in Inflammatory Bowel Disease 259\u003c\/p\u003e \u003cp\u003e10.6 Summary and Outlook 260\u003c\/p\u003e \u003cp\u003eReferences 261\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Hepatic Transport 277\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eKazuya Maeda, Hiroshi Suzuki, and Yuichi Sugiyama\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 278\u003c\/p\u003e \u003cp\u003e11.2 Hepatic Uptake 278\u003c\/p\u003e \u003cp\u003e11.2.1 NTCP (\u003ci\u003eSLC10A1\u003c\/i\u003e) 279\u003c\/p\u003e \u003cp\u003e11.2.2 OATP (\u003ci\u003eSLCO\u003c\/i\u003e) Family Transporters 279\u003c\/p\u003e \u003cp\u003e11.2.3 OAT (\u003ci\u003eSLC22\u003c\/i\u003e) Family Transporters 281\u003c\/p\u003e \u003cp\u003e11.2.4 OCT (\u003ci\u003eSLC22\u003c\/i\u003e) Family Transporters 284\u003c\/p\u003e \u003cp\u003e11.3 Biliary Excretion 284\u003c\/p\u003e \u003cp\u003e11.3.1 MDR1 (P-glycoprotein; ABCB1) 287\u003c\/p\u003e \u003cp\u003e11.3.2 MRP2 (\u003ci\u003eABCC2\u003c\/i\u003e) 287\u003c\/p\u003e \u003cp\u003e11.3.3 BCRP (\u003ci\u003eABCG2\u003c\/i\u003e) 289\u003c\/p\u003e \u003cp\u003e11.3.4 BSEP (\u003ci\u003eABCB11\u003c\/i\u003e) 290\u003c\/p\u003e \u003cp\u003e11.3.5 MATE1 (\u003ci\u003eSLC47A1\u003c\/i\u003e) 290\u003c\/p\u003e \u003cp\u003e11.4 Sinusoidal Efflux 290\u003c\/p\u003e \u003cp\u003e11.4.1 MRP3 (\u003ci\u003eABCC3\u003c\/i\u003e) 291\u003c\/p\u003e \u003cp\u003e11.4.2 MRP4 (\u003ci\u003eABCC4\u003c\/i\u003e) 291\u003c\/p\u003e \u003cp\u003e11.4.3 Other Transporters 293\u003c\/p\u003e \u003cp\u003e11.5 Prediction of Hepatobiliary Transport of Substrates from \u003ci\u003eIn Vitro\u003c\/i\u003e Data 294\u003c\/p\u003e \u003cp\u003e11.5.1 Prediction of Hepatic Uptake Process from \u003ci\u003eIn Vitro\u003c\/i\u003e Data 294\u003c\/p\u003e \u003cp\u003e11.5.2 Prediction of the Contribution of Each Transporter to the Overall Hepatic Uptake 295\u003c\/p\u003e \u003cp\u003e11.5.3 Prediction of Hepatic Efflux Process from In Vitro Data 298\u003c\/p\u003e \u003cp\u003e11.5.4 Utilization of Double (Multiple) Transfected Cells for the Characterization of Hepatobiliary Transport 299\u003c\/p\u003e \u003cp\u003e11.6 Genetic Polymorphism of Transporters and Its Clinical Relevance 301\u003c\/p\u003e \u003cp\u003e11.7 Transporter-Mediated Drug–Drug Interactions 305\u003c\/p\u003e \u003cp\u003e11.7.1 Effect of Drugs on the Activity of Uptake Transporters Located on the Sinusoidal Membrane 305\u003c\/p\u003e \u003cp\u003e11.7.2 Effect of Drugs on the Activity of Efflux Transporters Located on the Bile Canalicular Membrane 308\u003c\/p\u003e \u003cp\u003e11.7.3 Prediction of Drug–Drug Interaction from In Vitro Data 309\u003c\/p\u003e \u003cp\u003e11.8 Concluding Remarks 309\u003c\/p\u003e \u003cp\u003eReferences 311\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 The Importance of Gut Wall Metabolism in Determining Drug Bioavailability 333\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eChristopher Kohl\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 334\u003c\/p\u003e \u003cp\u003e12.2 Physiology of the Intestinal Mucosa 334\u003c\/p\u003e \u003cp\u003e12.3 Drug-Metabolizing Enzymes in the Human Mucosa 336\u003c\/p\u003e \u003cp\u003e12.3.1 Cytochrome P450 336\u003c\/p\u003e \u003cp\u003e12.3.2 Glucuronyltransferase 337\u003c\/p\u003e \u003cp\u003e12.3.3 Sulfotransferase 337\u003c\/p\u003e \u003cp\u003e12.3.4 Other Enzymes 337\u003c\/p\u003e \u003cp\u003e12.4 Oral Bioavailability 341\u003c\/p\u003e \u003cp\u003e12.4.1 \u003ci\u003eIn Vivo\u003c\/i\u003e Approaches to Differentiate Between Intestinal and Hepatic First-Pass Metabolism 342\u003c\/p\u003e \u003cp\u003e12.4.2 \u003ci\u003eIn Vitro\u003c\/i\u003e Approaches to Estimate Intestinal Metabolism 344\u003c\/p\u003e \u003cp\u003e12.4.3 Computational Approaches to Estimate and to Predict Human Intestinal Metabolism 345\u003c\/p\u003e \u003cp\u003e12.5 Clinical Relevance of Gut Wall First-Pass Metabolism 347\u003c\/p\u003e \u003cp\u003eReferences 347\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Modified Cell Lines 359\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eGuangqing Xiao and Charles L. Crespi\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 359\u003c\/p\u003e \u003cp\u003e13.2 Cell\/Vector Systems 360\u003c\/p\u003e \u003cp\u003e13.3 Expression of Individual Metabolic Enzymes 363\u003c\/p\u003e \u003cp\u003e13.4 Expression of Transporters 365\u003c\/p\u003e \u003cp\u003e13.4.1 Efflux Transporters 365\u003c\/p\u003e \u003cp\u003e13.4.2 Uptake Transporters 367\u003c\/p\u003e \u003cp\u003e13.5 Summary and Future Perspectives 368\u003c\/p\u003e \u003cp\u003eReferences 368\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart Four Computational Approaches to Drug Absorption and Bioavailability 373\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Calculated Molecular Properties and Multivariate Statistical Analysis 375\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eUlf Norinder\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 377\u003c\/p\u003e \u003cp\u003e14.2 Calculated Molecular Descriptors 377\u003c\/p\u003e \u003cp\u003e14.2.1 2D-Based Molecular Descriptors 377\u003c\/p\u003e \u003cp\u003e14.2.1.1 Constitutional Descriptors 378\u003c\/p\u003e \u003cp\u003e14.2.1.2 Fragment- and Functional Group-Based Descriptors 378\u003c\/p\u003e \u003cp\u003e14.2.1.3 Topological Descriptors 379\u003c\/p\u003e \u003cp\u003e14.2.2 3D Descriptors 381\u003c\/p\u003e \u003cp\u003e14.2.2.1 WHIM Descriptors 381\u003c\/p\u003e \u003cp\u003e14.2.2.2 Jurs Descriptors 382\u003c\/p\u003e \u003cp\u003e14.2.2.3 VolSurf and Almond Descriptors 383\u003c\/p\u003e \u003cp\u003e14.2.2.4 Pharmacophore Fingerprints 384\u003c\/p\u003e \u003cp\u003e14.2.3 Property-Based Descriptors 385\u003c\/p\u003e \u003cp\u003e14.2.3.1 log P 385\u003c\/p\u003e \u003cp\u003e14.2.3.2 HYBOT Descriptors 386\u003c\/p\u003e \u003cp\u003e14.2.3.3 Abraham Descriptors 386\u003c\/p\u003e \u003cp\u003e14.2.3.4 Polar Surface Area 386\u003c\/p\u003e \u003cp\u003e14.3 Statistical Methods 387\u003c\/p\u003e \u003cp\u003e14.3.1 Linear and Nonlinear Methods 388\u003c\/p\u003e \u003cp\u003e14.3.1.1 Multiple Linear Regression 388\u003c\/p\u003e \u003cp\u003e14.3.1.2 Partial Least Squares 389\u003c\/p\u003e \u003cp\u003e14.3.1.3 Artificial Neural Networks 390\u003c\/p\u003e \u003cp\u003e14.3.1.4 Bayesian Neural Networks 390\u003c\/p\u003e \u003cp\u003e14.3.1.5 Support Vector Machines 390\u003c\/p\u003e \u003cp\u003e14.3.1.6 k-Nearest Neighbor Modeling 392\u003c\/p\u003e \u003cp\u003e14.3.1.7 Linear Discriminant Analysis 392\u003c\/p\u003e \u003cp\u003e14.3.2 Partitioning Methods 393\u003c\/p\u003e \u003cp\u003e14.3.2.1 Traditional Rule-Based Methods 393\u003c\/p\u003e \u003cp\u003e14.3.2.2 Rule-Based Methods Using Genetic Programming 394\u003c\/p\u003e \u003cp\u003e14.3.3 Consensus and Ensemble Methods 395\u003c\/p\u003e \u003cp\u003e14.4 Applicability Domain 396\u003c\/p\u003e \u003cp\u003e14.5 Training and Test Set Selection and Model Validation 398\u003c\/p\u003e \u003cp\u003e14.5.1 Training and Test Set Selection 398\u003c\/p\u003e \u003cp\u003e14.5.2 Model Validation 399\u003c\/p\u003e \u003cp\u003e14.6 Future Outlook 400\u003c\/p\u003e \u003cp\u003eReferences 401\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Computational Absorption Prediction 409\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eChristel A.S. Bergström, Markus Haeberlein, and Ulf Norinder\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction 410\u003c\/p\u003e \u003cp\u003e15.2 Descriptors Influencing Absorption 410\u003c\/p\u003e \u003cp\u003e15.2.1 Solubility 411\u003c\/p\u003e \u003cp\u003e15.2.2 Membrane Permeability 412\u003c\/p\u003e \u003cp\u003e15.3 Computational Models of Oral Absorption 413\u003c\/p\u003e \u003cp\u003e15.3.1 Quantitative Predictions of Oral Absorption 413\u003c\/p\u003e \u003cp\u003e15.3.1.1 Responses: Evaluations of Measurement of Fraction Absorbed 417\u003c\/p\u003e \u003cp\u003e15.3.1.2 Model Development: Data sets, Descriptors, Technologies, and Applicability 419\u003c\/p\u003e \u003cp\u003e15.3.2 Qualitative Predictions of Oral Absorption 420\u003c\/p\u003e \u003cp\u003e15.3.2.1 Model Development: Data sets, Descriptors, Technologies, and Applicability 420\u003c\/p\u003e \u003cp\u003e15.3.2.2 An Example Using Genetic Programming-Based Rule Extraction 426\u003c\/p\u003e \u003cp\u003e15.3.3 Repeated Use of Data Sets 427\u003c\/p\u003e \u003cp\u003e15.4 Software for Absorption Prediction 427\u003c\/p\u003e \u003cp\u003e15.5 Future Outlook 428\u003c\/p\u003e \u003cp\u003eReferences 429\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 In Silico Prediction of Human Bioavailability 433\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eDavid J. Livingstone and Han van de Waterbeemd\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 434\u003c\/p\u003e \u003cp\u003e16.2 Concepts of Pharmacokinetics and Role of Oral Bioavailability 437\u003c\/p\u003e \u003cp\u003e16.3 \u003ci\u003eIn Silico\u003c\/i\u003e QSAR Models of Oral Bioavailability 438\u003c\/p\u003e \u003cp\u003e16.3.1 Prediction of Human Bioavailability 438\u003c\/p\u003e \u003cp\u003e16.3.2 Prediction of Animal Bioavailability 441\u003c\/p\u003e \u003cp\u003e16.4 Prediction of the Components of Bioavailability 441\u003c\/p\u003e \u003cp\u003e16.5 Using Physiological Modeling to Predict Oral Bioavailability 443\u003c\/p\u003e \u003cp\u003e16.6 Conclusions 445\u003c\/p\u003e \u003cp\u003eReferences 446\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Simulations of Absorption, Metabolism, and Bioavailability 453\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eMichael B. Bolger, Robert Fraczkiewicz, and Viera Lukacova\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction 454\u003c\/p\u003e \u003cp\u003e17.2 Background 454\u003c\/p\u003e \u003cp\u003e17.3 Use of Rule-Based Computational Alerts in Early Discovery 456\u003c\/p\u003e \u003cp\u003e17.3.1 Simple Rules for Drug Absorption (Druggability) 456\u003c\/p\u003e \u003cp\u003e17.3.2 Complex Rules That Include Toxicity 473\u003c\/p\u003e \u003cp\u003e17.4 Mechanistic Simulation (ACAT Models) in Early Discovery 474\u003c\/p\u003e \u003cp\u003e17.4.1 Automatic Scaling of k’\u003csub\u003ea\u003c\/sub\u003e 0 as a Function of P\u003csub\u003eeff\u003c\/sub\u003e, pH, log D, and GI Surface Area 477\u003c\/p\u003e \u003cp\u003e17.4.2 Mechanistic Corrections for Active Transport and Efflux 478\u003c\/p\u003e \u003cp\u003e17.4.3 PBPK and \u003ci\u003eIn Silico\u003c\/i\u003e Estimation of Distribution 481\u003c\/p\u003e \u003cp\u003e17.5 Mechanistic Simulation of Bioavailability (Drug Development) 481\u003c\/p\u003e \u003cp\u003e17.5.1 Approaches to \u003ci\u003eIn Silico\u003c\/i\u003e Estimation of Metabolism 484\u003c\/p\u003e \u003cp\u003e17.6 Regulatory Aspects of Modeling and Simulation (FDA Critical Path Initiative) 484\u003c\/p\u003e \u003cp\u003e17.7 Conclusions 485\u003c\/p\u003e \u003cp\u003eReferences 485\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 Toward Understanding P-Glycoprotein Structure–Activity Relationships 497\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eAnna Seelig\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 498\u003c\/p\u003e \u003cp\u003e18.1.1 Similarity Between P-gp and Other ABC Transporters 498\u003c\/p\u003e \u003cp\u003e18.1.2 Why P-gp Is Special 500\u003c\/p\u003e \u003cp\u003e18.2 Measurement of P-gp Function 500\u003c\/p\u003e \u003cp\u003e18.2.1 P-gp ATPase Activity Assay 500\u003c\/p\u003e \u003cp\u003e18.2.1.1 Quantification of Substrate–Transporter Interactions 503\u003c\/p\u003e \u003cp\u003e18.2.1.2 Relationship between Substrate–Transporter Affinity and Rate of Transport 504\u003c\/p\u003e \u003cp\u003e18.2.2 Transport Assays 506\u003c\/p\u003e \u003cp\u003e18.2.3 Competition Assays 508\u003c\/p\u003e \u003cp\u003e18.3 Predictive \u003ci\u003eIn Silico\u003c\/i\u003e Models 508\u003c\/p\u003e \u003cp\u003e18.3.1 Introduction to Structure–Activity Relationship 509\u003c\/p\u003e \u003cp\u003e18.3.2 3D-QSAR Pharmacophore Models 509\u003c\/p\u003e \u003cp\u003e18.3.3 Linear Discriminant Models 510\u003c\/p\u003e \u003cp\u003e18.3.4 Modular Binding Approach 511\u003c\/p\u003e \u003cp\u003e18.3.5 Rule-Based Approaches 512\u003c\/p\u003e \u003cp\u003e18.4 Discussion 513\u003c\/p\u003e \u003cp\u003e18.4.1 Prediction of Substrate-P-gp Interactions 513\u003c\/p\u003e \u003cp\u003e18.4.2 Prediction of ATPase Activity or Intrinsic Transport 513\u003c\/p\u003e \u003cp\u003e18.4.3 Prediction of Transport (i.e., Apparent Transport) 513\u003c\/p\u003e \u003cp\u003e18.4.4 Prediction of Competition 514\u003c\/p\u003e \u003cp\u003e18.4.5 Conclusions 514\u003c\/p\u003e \u003cp\u003eReferences 514\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart Five Drug Development Issues 521\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19 Application of the Biopharmaceutics Classification System Now and in the Future 523\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eBertil Abrahamsson and Hans Lennernäs\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 524\u003c\/p\u003e \u003cp\u003e19.2 Definition of Absorption and Bioavailability of Drugs Following Oral Administration 527\u003c\/p\u003e \u003cp\u003e19.3 Dissolution and Solubility 528\u003c\/p\u003e \u003cp\u003e19.4 The Effective Intestinal Permeability (P\u003csub\u003eeff\u003c\/sub\u003e) 535\u003c\/p\u003e \u003cp\u003e19.5 Luminal Degradation and Binding 539\u003c\/p\u003e \u003cp\u003e19.6 The Biopharmaceutics Classification System 541\u003c\/p\u003e \u003cp\u003e19.6.1 Regulatory Aspects 541\u003c\/p\u003e \u003cp\u003e19.6.1.1 Present Situation 541\u003c\/p\u003e \u003cp\u003e19.6.1.2 Potential Future Extensions 543\u003c\/p\u003e \u003cp\u003e19.6.2 Drug Development Aspects 543\u003c\/p\u003e \u003cp\u003e19.6.2.1 Selection of Candidate Drugs 544\u003c\/p\u003e \u003cp\u003e19.6.2.2 Choice of Formulation Principle 545\u003c\/p\u003e \u003cp\u003e19.6.2.3 In Vitro\/In Vivo Correlation 547\u003c\/p\u003e \u003cp\u003e19.6.2.4 Food–Drug Interactions 549\u003c\/p\u003e \u003cp\u003e19.6.2.5 Quality by Design 552\u003c\/p\u003e \u003cp\u003e19.7 Conclusions 552\u003c\/p\u003e \u003cp\u003eReferences 553\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20 Prodrugs 559\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eBernard Testa\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction 559\u003c\/p\u003e \u003cp\u003e20.2 Why Prodrugs? 560\u003c\/p\u003e \u003cp\u003e20.2.1 Pharmaceutical Objectives 560\u003c\/p\u003e \u003cp\u003e20.2.2 Pharmacokinetic Objectives 561\u003c\/p\u003e \u003cp\u003e20.2.3 Pharmacodynamic Objectives 564\u003c\/p\u003e \u003cp\u003e20.3 How Prodrugs? 565\u003c\/p\u003e \u003cp\u003e20.3.1 Types of Prodrugs 565\u003c\/p\u003e \u003cp\u003e20.3.2 Hurdles in Prodrug Research 567\u003c\/p\u003e \u003cp\u003e20.4 Conclusions 568\u003c\/p\u003e \u003cp\u003eReferences 568\u003c\/p\u003e \u003cp\u003e\u003cb\u003e21 Modern Delivery Strategies: Physiological Considerations for Orally Administered Medications 571\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eClive G. Wilson and Werner Weitschies\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e21.1 Introduction 571\u003c\/p\u003e \u003cp\u003e21.2 The Targets 572\u003c\/p\u003e \u003cp\u003e21.3 The Upper GI Tract: Mouth and Esophagus 573\u003c\/p\u003e \u003cp\u003e21.3.1 Swallowing the Bitter Pill... 575\u003c\/p\u003e \u003cp\u003e21.4 Mid-GI Tract: Stomach and Intestine 576\u003c\/p\u003e \u003cp\u003e21.4.1 Gastric Inhomogeneity 576\u003c\/p\u003e \u003cp\u003e21.4.2 Gastric Emptying 579\u003c\/p\u003e \u003cp\u003e21.4.3 Small Intestinal Transit Patterns 581\u003c\/p\u003e \u003cp\u003e21.4.4 Modulation of Transit to Prolong the Absorption Phase 582\u003c\/p\u003e \u003cp\u003e21.4.5 Absorption Enhancement 582\u003c\/p\u003e \u003cp\u003e21.5 The Lower GI Tract: The Colon 583\u003c\/p\u003e \u003cp\u003e21.5.1 Colonic Transit 584\u003c\/p\u003e \u003cp\u003e21.5.2 Time of Dosing 585\u003c\/p\u003e \u003cp\u003e21.5.3 Modulating Colonic Water 586\u003c\/p\u003e \u003cp\u003e21.6 Pathophysiological Effects on Transit 587\u003c\/p\u003e \u003cp\u003e21.7 Pathophysiological Effects on Permeability 589\u003c\/p\u003e \u003cp\u003e21.8 pH 589\u003c\/p\u003e \u003cp\u003e21.9 Conclusions 590\u003c\/p\u003e \u003cp\u003eReferences 590\u003c\/p\u003e \u003cp\u003e\u003cb\u003e22 Nanotechnology for Improved Drug Bioavailability 597\u003cbr\u003e\u003c\/b\u003e\u003ci\u003eMarjo Yliperttula and Arto Urtti\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e22.1 Introduction 597\u003c\/p\u003e \u003cp\u003e22.2 Nanotechnological Systems in Drug Delivery 599\u003c\/p\u003e \u003cp\u003e22.2.1 Classification of the Technologies 599\u003c\/p\u003e \u003cp\u003e22.2.1.1 Nanocrystals 599\u003c\/p\u003e \u003cp\u003e22.2.1.2 Self-Assembling Nanoparticulates 600\u003c\/p\u003e \u003cp\u003e22.2.1.3 Processed Nanoparticulates 601\u003c\/p\u003e \u003cp\u003e22.2.1.4 Single-Molecule-Based Nanocarriers 601\u003c\/p\u003e \u003cp\u003e22.2.2 Pharmaceutical Properties of Nanotechnological Formulations 601\u003c\/p\u003e \u003cp\u003e22.2.2.1 Drug-Loading Capacity 601\u003c\/p\u003e \u003cp\u003e22.2.2.2 Processing 602\u003c\/p\u003e \u003cp\u003e22.2.2.3 Biological Stability 602\u003c\/p\u003e \u003cp\u003e22.3 Delivery via Nanotechnologies 603\u003c\/p\u003e \u003cp\u003e22.3.1 Delivery Aspects at Cellular Level 603\u003c\/p\u003e \u003cp\u003e22.3.2 Nanosystems for Improved Oral Drug Bioavailability 606\u003c\/p\u003e \u003cp\u003e22.3.3 Nanosystems for Improved Local Drug Bioavailability 606\u003c\/p\u003e \u003cp\u003e22.4 Key Issues and Future Prospects 608\u003c\/p\u003e \u003cp\u003eReferences 609\u003c\/p\u003e \u003cp\u003eIndex 613\u003c\/p\u003e","brand":"Wiley-VCH Verlag GmbH","offers":[{"title":"Default Title","offer_id":53196946342231,"sku":"9783527320516","price":207.86,"currency_code":"GBP","in_stock":true}],"url":"https:\/\/bookcurl.com\/products\/drug-bioavailability-estimation-of-solubility-permeability-absorption-and-bioavailability-9783527320516","provider":"Book Curl","version":"1.0","type":"link"}