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Book Details
Abstract
Understanding and quantifying the effects of membrane transporters within the human body is essential for modulating drug safety and drug efficacy. The first volume comprehensively reviewed current knowledge and techniques in the transporter sciences and their relations to drug metabolism and pharmacokinetics. In this second volume on Drug Transporters, emphasis is placed on emerging sciences and technologies, highlighting potential areas for future advances within the drug transporter field.
The topics covered in both volumes ensure that all relevant aspects of transporters are described across the drug development process, from in silico models and preclinical tools through to the potential impact of transporters in the clinic. Contributions are included from expert leaders in the field, at-the-bench industrial scientists, renowned academics and international regulators. Case studies and emerging developments are highlighted, together with the merits and limitations of the available methods and tools, and extensive references to reviews on specific in-depth topics are also included for those wishing to pursue their knowledge further.
As such, this text serves as an essential handbook of information for postgraduate students, academics, industrial scientists and regulators who wish to understand the role of transporters in absorption, distribution, metabolism, and excretion processes. In addition, it is also a useful reference tool on the models and calculations necessary to predict their effect on human pharmacokinetics and pharmacodynamics.
Dr Glynis Nicholls has over 18 years experience within the pharmaceutical field in both academia and industry (including 7 years at GlaxoSmithKline and 5 years at AstraZeneca), specializing in drug transporter science from discovery through to clinical development. Dr Nicholls has played a leading role in writing and implementing internal transporter strategies within the industry, as well as collaborating across multiple international locations with internal and external colleagues on transporter-related projects and scientific developments, including PhD projects. Dr Kuresh Youdim has 9 years academic experience in the field of nutrition and neuroscience, plus 10 years pharmaceutical experience across multiple disciplines within drug discovery and development (including 8 years at Pfizer and 2 years at Roche) predominantly in the field of drug-drug interactions and PBPK modelling.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Contents | xvii | ||
| Preface | vii | ||
| Acknowledgements | ix | ||
| Abbreviations | x | ||
| Chapter 1 Emerging Transporter Science and Challenges for the Future | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 Membrane Transporters of Emerging Importance | 2 | ||
| 1.3 Membrane Transporters in Less-studied Organs and Tissues | 3 | ||
| 1.3.1 Placenta | 3 | ||
| 1.3.2 Retina | 4 | ||
| 1.3.3 Heart | 5 | ||
| 1.3.4 Skin | 6 | ||
| 1.4 Organotypic In vitro Technologies | 6 | ||
| 1.4.1 Microfluidics | 7 | ||
| 1.4.2 3D Microplatforms | 9 | ||
| 1.4.3 3D Bioprinting | 9 | ||
| 1.5 Summary | 10 | ||
| References | 11 | ||
| Chapter 2 Enabling Dynamic Response to Chemical Challenge: Nuclear Receptor-mediated Control of Transporter Expression | 19 | ||
| 2.1 General Introduction | 19 | ||
| 2.2 Nuclear Receptor Overview | 20 | ||
| 2.2.1 General Introduction | 20 | ||
| 2.2.2 Structure of Nuclear Receptors | 21 | ||
| 2.3 Localisation and Function of Nuclear Receptors | 24 | ||
| 2.3.1 Trans-activation | 25 | ||
| 2.3.2 Trans-repression | 26 | ||
| 2.4 Nuclear Receptors as Chemical Sensors | 27 | ||
| 2.5 Nuclear Receptors and Drug Transporters | 29 | ||
| 2.6 The ABC Superfamily | 29 | ||
| 2.6.1 ABCA Subfamily | 30 | ||
| 2.6.2 ABCB Subfamily | 30 | ||
| 2.6.3 ABCC Subfamily | 31 | ||
| 2.6.4 ABCD Subfamily | 32 | ||
| 2.6.5 ABCE and ABCF Subfamilies | 32 | ||
| 2.6.6 ABCG Subfamily | 32 | ||
| 2.7 SLC Superfamily | 33 | ||
| 2.7.1 Oligopeptide Transporters (SLC15A) | 33 | ||
| 2.7.2 Folate Transporters (SLC19A) | 33 | ||
| 2.7.3 Concentrative Nucleoside Transporters (SLC28A) | 34 | ||
| 2.7.4 Equilibrative Nucleoside Transporters (SLC29A) | 34 | ||
| 2.7.5 Organic Anion Transporters (SLCO/SLC21) | 35 | ||
| 2.7.6 Organic Cation Transporters (SLC22) | 35 | ||
| 2.7.7 Multidrug and Toxin Extrusion Proteins (SLC47) | 36 | ||
| 2.8 Conclusion | 36 | ||
| References | 37 | ||
| Chapter 3 Targeted Proteomics to Support Transporter IVIVE and PBPK | 44 | ||
| 3.1 Introduction | 44 | ||
| 3.1.1 In vitro to In vivo Extrapolation (IVIVE) of Transporter Activity | 46 | ||
| 3.2 Methods for Quantitative Proteomics | 48 | ||
| 3.2.1 Mass Spectrometry-based Proteomics | 48 | ||
| 3.3 Utility of Transporter Proteomic Data in the Translation of Transporter Activity in Human Tissues | 56 | ||
| 3.3.1 IVIVE of Actively Transported Substrate Drugs | 56 | ||
| 3.3.2 IVIVE and PBPK of Hepatobiliary Transport | 57 | ||
| 3.3.3 IVIVE and PBPK of Intestinal Transport | 60 | ||
| 3.3.4 IVIVE and PBPK of Transport Through the Blood-Brain Barrier | 61 | ||
| 3.3.5 IVIVE and PBPK of Renal Transport | 62 | ||
| 3.4 Current Status and Future Challenges | 63 | ||
| References | 65 | ||
| Chapter 4 Interplay Between Enzymes and Transporters: Impact on the Prediction of Pharmacokinetics and Drug–Drug Interactions | 73 | ||
| 4.1 Introduction | 73 | ||
| 4.2 Evidence of the Clinical Impact of the Interplay Between Enzymes and Transporters | 76 | ||
| 4.2.1 Impact of the Interplay Between Enzymes and Transporters on Absorption | 76 | ||
| 4.2.2 Impact of the Interplay Between Enzymes and Transporters on Distribution | 80 | ||
| 4.2.3 Impact of the Interplay Between Enzymes and Transporters on Elimination | 82 | ||
| 4.2.4 Interplay Due to Regulation of Enzymes and Transporters | 85 | ||
| 4.3 Prediction of the Impact of the Interplay Between Enzymes and Transporters on Pharmacokinetics | 87 | ||
| 4.3.1 Preclinical Investigation of the Enzyme-Transporter Interplay | 87 | ||
| 4.3.2 Applications and Limitations of Traditional Physiological Models for In vitro–In vivo Extrapolation in the Case of Interplay Between Enzymes and Transporters | 92 | ||
| 4.3.3 Application of PBPK Modelling to Predict the Impact of the Enzyme–Transporter Interplay | 94 | ||
| 4.4 Prediction of Complex DDIs Involving CYP450 and Transporters | 97 | ||
| 4.5 Conclusions | 99 | ||
| Acknowledgments | 100 | ||
| References | 100 | ||
| Chapter 5 Pharmacogenomics of Drug Transporters: Clinical Implications | 114 | ||
| 5.1 Introduction | 114 | ||
| 5.2 Pharmacogenomics and Transporters | 115 | ||
| 5.3 Pharmacogenomics of Current Clinically-relevant Transporters | 117 | ||
| 5.3.1 OATP1B1 (SLCO1B1) | 117 | ||
| 5.3.2 OATP1B3 (SLCO1B3) | 120 | ||
| 5.3.3 OATP2B1 (SLCO2B1) | 120 | ||
| 5.3.4 MATE1 (SLC47A1) | 123 | ||
| 5.3.5 MATE2-K (SLC47A2) | 125 | ||
| 5.3.6 BCRP (ABCG2) | 125 | ||
| 5.3.7 MDR1 (P-glycoprotein, ABCB1) | 127 | ||
| 5.3.8 OATs (SLC22A) | 127 | ||
| 5.3.9 OCTs (SLC22A) | 133 | ||
| 5.4 Pharmacogenomics of Other Transporters of Interest | 136 | ||
| 5.4.1 MRP2 (ABCC2) | 136 | ||
| 5.4.2 BSEP (ABCB11) | 136 | ||
| 5.5 Conclusion | 136 | ||
| References | 137 | ||
| Chapter 6 The Role of In vivo Imaging in the Study of Transporter Interactions in Animals and Humans | 143 | ||
| 6.1 Introduction | 143 | ||
| 6.2 In vivo Imaging within Drug Development | 145 | ||
| 6.3 Pharmacokinetic and Pharmacodynamic Imaging Techniques | 147 | ||
| 6.3.1 Magnetic Resonance Imaging (MRI) | 147 | ||
| 6.3.2 Radionuclide Imaging | 152 | ||
| 6.3.3 Multimodality Imaging | 157 | ||
| 6.4 The Application of Imaging in Evaluating Transporter Drug–Drug Interactions | 158 | ||
| 6.4.1 Blood-Brain Barrier (BBB) | 159 | ||
| 6.4.2 Liver | 162 | ||
| 6.4.3 Kidney | 167 | ||
| 6.4.4 Gastrointestinal (GI) Tract | 169 | ||
| 6.4.5 Imaging in Other ADME Organs | 170 | ||
| 6.5 The Use of Imaging to Assess Transporter Function and Expression In vivo | 170 | ||
| 6.6 Personalised Healthcare: Potential Applications | 172 | ||
| 6.7 Future Perspectives | 173 | ||
| References | 174 | ||
| Chapter 7 Methods and Resources for Transport Proteins in Bioinformatics and Cheminformatics | 195 | ||
| 7.1 Introduction | 195 | ||
| 7.2 Bioinformatics Methods | 196 | ||
| 7.2.1 Transporter Classification | 197 | ||
| 7.2.2 Data Integration | 198 | ||
| 7.3 Cheminformatics Methods | 199 | ||
| 7.3.1 Ligand-based Methods | 199 | ||
| 7.3.2 Structure-based Methods | 204 | ||
| 7.4 Resources | 205 | ||
| 7.4.1 Resourceome for the Transportome | 205 | ||
| 7.4.2 Transporter Data Sources in Drug Discovery | 213 | ||
| 7.5 Conclusions | 215 | ||
| References | 216 | ||
| Subject Index | 227 |