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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. In this first volume on Drug Transporters, the current knowledge and techniques in the transporter sciences and their relations to drug metabolism and pharmacokinetics are comprehensively reviewed. The second volume of the book is specifically dedicated to emerging science 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 | ||
| Section I: The Role of Transporters in ADME | 1 | ||
| Chapter 1 Membrane Transporters: Fundamentals, Function and Their Role in ADME | 3 | ||
| 1.1 Introduction | 3 | ||
| 1.2 The History of Transporter Science | 4 | ||
| 1.2.1 The Discovery of Transport Processes | 4 | ||
| 1.2.2 The Development of Transporter Science in Industry | 6 | ||
| 1.3 Transporter Form and Function | 10 | ||
| 1.3.1 Transporter Families and Nomenclature | 10 | ||
| 1.3.2 Driving Forces for ABCs and SLCs | 12 | ||
| 1.3.3 Uptake, Efflux and Bi-directionality | 14 | ||
| 1.3.4 Substrate Specificities and Binding Sites | 14 | ||
| 1.3.5 Transporter Localisation and Interplay | 16 | ||
| 1.3.6 Transporter Expression in Animal Species | 18 | ||
| 1.3.7 Other Factors Affecting Transporter Form and Function | 19 | ||
| 1.4 The Transporter Toolkit | 23 | ||
| 1.4.1 In Situ and In Vitro Models: Basic Concepts, Limitations and Translation | 23 | ||
| 1.4.2 In Vitro Transporter Inhibition Studies | 25 | ||
| 1.4.3 In Vitro Transporter Substrate Studies | 26 | ||
| 1.4.4 In Vitro Transporter Induction Studies | 26 | ||
| 1.4.5 In Vivo Studies in Preclinical Species and Humans | 27 | ||
| 1.4.6 Metabolite-Transporter Interactions | 27 | ||
| 1.5 Drug Transporters and PK | 28 | ||
| 1.5.1 Permeability | 28 | ||
| 1.5.2 Oral Absorption and Bioavailability | 29 | ||
| 1.5.3 Drug Clearance | 31 | ||
| 1.6 Evaluating and Interpreting Drug Transporter Interactions in Drug Discovery and Development | 33 | ||
| 1.6.1 Drug Discovery Approaches | 34 | ||
| 1.6.2 Drug Development Approaches | 37 | ||
| 1.7 Toxicity and Transporters | 40 | ||
| 1.8 Conclusions and Future Directions | 41 | ||
| References | 42 | ||
| Chapter 2 Drug Transporters in the Liver: Their Involvement in the Uptake and Export of Endo- and Xeno-biotics | 57 | ||
| 2.1 Introduction | 57 | ||
| 2.2 Solute Carrier Superfamily Members Expressed in Hepatocytes | 60 | ||
| 2.2.1 The SLCO Family of OATPs | 60 | ||
| 2.2.2 The SLC22 Family of OCTs and OATs | 64 | ||
| 2.2.3 SLC10: the Sodium Bile Salt Cotransporter Family | 66 | ||
| 2.2.4 Multidrug and Toxin Extrusion (MATE) Family (SLC47) | 66 | ||
| 2.2.5 The Heterodimeric OSTα/OSTβ in the SLC51 Family \r | 66 | ||
| 2.3 ABC Transporters in Hepatocytes | 67 | ||
| 2.3.1 MRP3 (ABCC3) | 68 | ||
| 2.3.2 MRP4 (ABCC4) | 68 | ||
| 2.3.3 MRP6 (ABCC6) | 69 | ||
| 2.3.4 MDR1 (ABCB1) | 69 | ||
| 2.3.5 ABCG2 (BCRP, ABCG2) | 70 | ||
| 2.3.6 MRP2 (ABCC2) | 70 | ||
| 2.3.7 BSEP (ABCC11) | 70 | ||
| 2.4 Implications for Drug Development | 71 | ||
| 2.5 Summary and Conclusions | 73 | ||
| References | 73 | ||
| Chapter 3 Drug Transporters in the Intestine | 81 | ||
| 3.1 The Intestinal Tract and Drug Absorption | 81 | ||
| 3.2 The Enterocyte Monolayer | 85 | ||
| 3.3 Drug Transporters in Absorption | 89 | ||
| 3.4 Conclusions | 92 | ||
| References | 103 | ||
| Chapter 4 Drug Transporters in the Kidney | 109 | ||
| 4.1 Introduction | 109 | ||
| 4.2 The Anatomy of the Kidney | 110 | ||
| 4.3 Renal Clearance of Xenobiotic Compounds | 112 | ||
| 4.4 Drug Transporter Expression in the Proximal Tubule | 114 | ||
| 4.4.1 OATs | 115 | ||
| 4.4.2 OATPs | 121 | ||
| 4.4.3 Organic Anion Transporters URAT1, GLUT9 and NPT4 | 122 | ||
| 4.4.4 OCTs | 123 | ||
| 4.4.5 MATEs | 124 | ||
| 4.4.6 MDR1 | 125 | ||
| 4.4.7 BCRP | 126 | ||
| 4.4.8 MRPs | 128 | ||
| 4.4.9 Peptide Transporters (PEPT1 and PEPT2) | 129 | ||
| 4.4.10 Phosphate Transporters | 130 | ||
| 4.4.11 Receptor-mediated Endocytosis (Megalin and Cubilin) | 130 | ||
| 4.5 In vitro Renal Models | 131 | ||
| 4.5.1 Xenopus Laevis Oocyte Expression System | 132 | ||
| 4.5.2 Transfected and Immortalized Renal Cell Lines | 132 | ||
| 4.5.3 Cortical Renal Slices | 133 | ||
| 4.5.4 Primary Proximal Tubular Cells | 133 | ||
| 4.6 Species Differences in Renal Handling | 134 | ||
| 4.7 Development of Predictive In vitro Models of Drug Transport | 135 | ||
| 4.8 Conclusion | 137 | ||
| References | 137 | ||
| Chapter 5 Drug Transporters at the Blood–Brain Barrier | 151 | ||
| 5.1 The Blood–Brain Barrier | 151 | ||
| 5.1.1 Overview | 151 | ||
| 5.1.2 BBB in Numbers | 152 | ||
| 5.1.3 Neurovascular Unit | 152 | ||
| 5.1.4 Physical Barrier | 154 | ||
| 5.1.5 Transport at the BBB | 156 | ||
| 5.2 Modelling of the BBB | 157 | ||
| 5.2.1 Cellular Models of the BBB | 157 | ||
| 5.2.2 In vivo Models | 158 | ||
| 5.3 Efflux Transporters Expressed at the BBB | 160 | ||
| 5.3.1 P-gp | 160 | ||
| 5.3.2 BCRP | 163 | ||
| 5.3.3 MRP4 | 164 | ||
| 5.3.4 Putatively Expressed BBB Efflux Transporters | 165 | ||
| 5.3.5 Interplay Between Efflux Transporters | 165 | ||
| 5.4 Influx Transporters Expressed at the BBB | 167 | ||
| 5.4.1 LAT1 | 167 | ||
| 5.4.2 Organic Anion Transporting Polypeptide Transporters | 168 | ||
| 5.4.3 Monocarboxylate Transporters | 169 | ||
| 5.4.4 Organic Cation Transporters | 169 | ||
| 5.4.5 Organic Anion Transporters | 170 | ||
| 5.4.6 Nutrient Transporters | 171 | ||
| 5.5 Transporters Expressed at the CP | 171 | ||
| 5.6 Challenge | 172 | ||
| 5.7 Opportunity | 173 | ||
| 5.8 Summary | 174 | ||
| References | 174 | ||
| Chapter 6 Drug Transporters in the Lung: Expression and Potential Impact on Pulmonary Drug Disposition | 184 | ||
| 6.1 Introduction | 184 | ||
| 6.2 The Lung: Anatomy, Morphology and Physiology | 185 | ||
| 6.2.1 Overview | 185 | ||
| 6.2.2 The Healthy Lung | 186 | ||
| 6.2.3 The Diseased Lung | 188 | ||
| 6.3 Inhalation Therapy and Pulmonary Drug Disposition | 189 | ||
| 6.4 Drug Transporter Families in the Human Lung | 192 | ||
| 6.5 In vitro and In vivo Models to Study Pulmonary Drug Disposition | 198 | ||
| 6.5.1 Cell Culture Models | 198 | ||
| 6.5.2 Isolated Perfused Lung Ex vivo | 202 | ||
| 6.5.3 In vivo Models | 204 | ||
| 6.6 Drug Transporters and Their Potential Impact on Inhaled Drug Disposition, Efficacy and Toxicity | 205 | ||
| 6.6.1 OCTs of the SLC22A Family | 205 | ||
| 6.6.2 Peptide Transporters of the SLC15A Family | 208 | ||
| 6.6.3 Other Transporters of the SLC and SLCO Families | 209 | ||
| 6.6.4 MDRs: P-gp | 211 | ||
| 6.6.5 MRPs: MRP1 | 213 | ||
| 6.6.6 BCRP | 214 | ||
| 6.7 Distribution of Drugs from the Systemic Circulation | 215 | ||
| 6.8 Transporter Regulation in the Lung | 216 | ||
| 6.9 Summary and Concluding Remarks | 217 | ||
| 6.10 Contributions by the Authors | 218 | ||
| References | 218 | ||
| Section II: Preclinical Models in Current Use within the Pharmaceutical Industry | 229 | ||
| Chapter 7 The Characteristics, Validation and Applications of In silico and In vitro Models of Drug Transporters | 231 | ||
| 7.1 Introduction | 231 | ||
| 7.2 In silico Models of Drug Transporters | 234 | ||
| 7.2.1 Why In silico Modelling? | 234 | ||
| 7.2.2 Transporter-based Methods | 241 | ||
| 7.2.3 Compound-based Methods | 244 | ||
| 7.3 In vitro Models of Transporters | 247 | ||
| 7.3.1 Membrane-based Models: Transport Assays Utilising Vesicles and the ATPase Assay | 247 | ||
| 7.3.2 Cell-based Models: Genetically Modified Cells | 251 | ||
| 7.3.3 Cell-based Models: Immortalised Cell Lines | 254 | ||
| 7.3.4 Cultures of Primary Cells | 255 | ||
| 7.3.5 Specialised Culture Formats | 260 | ||
| 7.3.6 Precision-cut Tissue Slices | 263 | ||
| 7.3.7 Isolated Perfused Organ Systems and Tissue Chambers | 265 | ||
| 7.4 Validation, Variability and Recommendations for Experimental Design of In vitro Assays | 267 | ||
| 7.4.1 Recommendations for Experimental Design | 268 | ||
| 7.4.2 General Considerations for Validating Transporter Substrate Assays | 268 | ||
| 7.4.3 General Considerations for Validating Transporter Inhibition Assays | 273 | ||
| 7.5 In vitro Parameters and Calculations for Kinetics and Predictions | 278 | ||
| 7.5.1 Kinetic Parameters Derived from In vitro Models | 278 | ||
| 7.5.2 In vitro Parameters in DDI Predictions | 280 | ||
| 7.6 Summary | 286 | ||
| Conflict of Interest | 286 | ||
| References | 286 | ||
| Chapter 8 Knockout and Humanised Animal Models to Study Membrane Transporters in Drug Development | 298 | ||
| 8.1 Introduction | 298 | ||
| 8.2 Methods for Generating Transporter Knockout and Humanised Animal Models for Use in Drug Development | 304 | ||
| 8.2.1 Transporter Knockout Animals | 304 | ||
| 8.2.2 Genetically Humanised Transporter Models | 306 | ||
| 8.2.3 Liver Humanised Animal Models | 308 | ||
| 8.3 Knockout and Humanised Animal Models in the Study of Transporter-mediated Drug Disposition | 309 | ||
| 8.3.1 Use of Transporter Knockout Animals to Study Efflux Transporter-limited Absorption | 310 | ||
| 8.3.2 Fraction Transported Determination using Transporter Knockout Animals: Insight into Transporter-mediated DDI Potential | 312 | ||
| 8.3.3 Use of Transporter Knockout Animals to Study Brain Distribution | 313 | ||
| 8.3.4 Use of Transporter Knockout Animals to Study Hepatic Uptake | 314 | ||
| 8.3.5 Use of Transporter Knockout Animals to Study Excretory Clearance | 316 | ||
| 8.3.6 Utility of Genetically Humanised Mouse Models | 318 | ||
| 8.3.7 Utility of Liver Humanised Mouse Models | 320 | ||
| 8.4 Study Design and Data Interpretation | 321 | ||
| 8.5 Conclusions and Perspectives | 324 | ||
| Declaration of Interest | 325 | ||
| References | 325 | ||
| Chapter 9 Mechanistic Modelling to Predict Transporter-mediated Drug Disposition and Drug–Drug Interactions | 333 | ||
| 9.1 Introduction | 333 | ||
| 9.2 Use of In vitro Methods to Estimate Transport Kinetics of Drugs | 336 | ||
| 9.2.1 Basic (Static) Approaches to Estimate Active and Passive Transport | 337 | ||
| 9.2.2 Mechanistic (Dynamic) Approaches to Delineate Hepatic Uptake, Efflux and Metabolism | 338 | ||
| 9.2.3 Permeability Models for Assessing Cellular Efflux and Transport | 339 | ||
| 9.3 Pharmacokinetic Models for Hepatic Transporter Substrates | 341 | ||
| 9.3.1 Static Model | 341 | ||
| 9.3.2 Empirical Compartment Model and Reduced PBPK Model | 342 | ||
| 9.3.3 Whole Body PBPK Model | 342 | ||
| 9.3.4 Characteristics and Applications of Different Pharmacokinetic Models for Transporter Substrates | 343 | ||
| 9.3.5 Pharmacokinetic Prediction and IVIVE of Transporter Activity | 344 | ||
| 9.3.6 Determining Values of Other Key Parameters in PBPK Models | 346 | ||
| 9.4 Transporter-mediated DDIs | 348 | ||
| 9.4.1 Static Approaches | 349 | ||
| 9.4.2 Dynamic Approaches | 351 | ||
| 9.4.3 Limitations of Current Approaches for DDI Predictions | 353 | ||
| 9.5 Summary | 354 | ||
| References | 354 | ||
| Section III: Importance and Clinical Impact of Transporter-mediated Drug–Drug Interactions | 361 | ||
| Chapter 10 Transporter Drug-Drug Interactions: A Pharmaceutical Industry Perspective | 363 | ||
| 10.1 Introduction and Overview of Clinical Drug-Drug Interactions | 363 | ||
| 10.1.1 DDIs in the Intestine | 365 | ||
| 10.1.2 DDIs in the Liver | 378 | ||
| 10.1.3 DDIs at the Blood–Brain Barrier | 379 | ||
| 10.1.4 DDIs in the Kidney | 381 | ||
| 10.1.5 DDIs in Other Tissues | 383 | ||
| 10.2 Transporter Assessment Strategies | 384 | ||
| 10.2.1 Which Transporters to Focus on for DDI Assessment: ITC Recommendations and Regulatory Requirements | 384 | ||
| 10.2.2 When to Investigate Risk for DDIs: Approaches in Transporter Assessment Strategies | 386 | ||
| 10.3 Clinical Interaction Studies | 390 | ||
| 10.3.1 Introduction | 390 | ||
| 10.3.2 Absorption | 395 | ||
| 10.3.3 Tissue Distribution | 397 | ||
| 10.3.4 Hepatic Clearance | 397 | ||
| 10.3.5 Renal Elimination | 398 | ||
| 10.4 Case Studies | 400 | ||
| 10.4.1 Digoxin DDIs | 400 | ||
| 10.4.2 Role of OATP1B1 in Statin DDIs | 402 | ||
| 10.5 Conclusion and Outlook | 404 | ||
| 10.5.1 Tailored, Step-wise Drug Transporter Testing Strategies in Drug Development | 404 | ||
| 10.5.2 Gaps Within In vitro Drug Transporter Tools | 405 | ||
| 10.5.3 The Challenge of Translating In vitro Drug Transporter Data to the Clinical Situation | 406 | ||
| Acknowledgments | 407 | ||
| References | 407 | ||
| Chapter 11 Transporter Drug-Drug Interactions: Regulatory Requirements and Drug Labelling | 418 | ||
| 11.1 Introduction | 418 | ||
| 11.2 New Drug Applications | 420 | ||
| 11.2.1 New Drug Applications to the EMA | 420 | ||
| 11.2.2 New Drug Applications to the FDA | 421 | ||
| 11.2.3 New Drug Applications to the MHLW/PMDA | 421 | ||
| 11.2.4 Transporter Sections in New Drug Applications | 423 | ||
| 11.2.5 Scientific Advice on New Drug Applications | 423 | ||
| 11.3 Regulatory Guidelines | 426 | ||
| 11.3.1 History of Transporters in Regulatory Guidelines | 426 | ||
| 11.3.2 European (EMA) Guidance | 427 | ||
| 11.3.3 Draft FDA Guidance | 439 | ||
| 11.3.4 Draft MHLW Guideline | 442 | ||
| 11.4 Conclusion | 446 | ||
| Disclaimer | 446 | ||
| Acknowledgments | 446 | ||
| References | 447 | ||
| Subject Index | 450 |