Search for the best prices     on the Internet!

An invaluable guide for pharmacology students and professionals which will help to reinforce the theory in the subject of drug metabolism, and help develop valuable analytical and interpreting skills.

Table of Contents:

Editor's preface xiii
Preface xiv
Grieves Harnby: In memoriam xv
Chapter 1 Introduction 1
1.1 Bioanalysis, pharmacokinetics and drug metabolism (BPDM) 1
1.2 The role of BPDM in drug discovery and drug development 2
Chapter 2 The Importance of the Physicochemical Properties of Drugs to Drug Metabolism 8
2.1 Introduction 8
2.2 The physicochemical nature of drug molecules 9
2.3 The structure of the cell membrane and its implications for drug disposition 10
2.4 Drug partitioning across membranes 11
2.5 The ionisation of drugs 13
2.6 The pH environment of the body and how it affects drug absorption and distribution 17
2.7 The importance of the physicochemical properties of drugs to their metabolism and excretion 20
2.8 Chirality and its effects on drug absorption, metabolism and excretion 24
2.9 The importance of physicochemical properties to the analysis of drugs 27
2.10 Summary 29
2.11 Bibliography 29
Chapter 3 Sample Preparation 32
3.1 Introduction 32
3.2 Sample preparation techniques 32
3.3 Instrumentation 35
3.4 Bioanalytical automation strategy 36
3.5 Future development 42
3.6 References 43
Chapter 4 High-Performance Liquid Chromatography in Pharmaceutical Bioanalysis 45
4.1 Introduction 45
4.2 A brief look at the theory of chromatographic separation in HPLC 46
4.3 The basic equipment comprising a modern HPLC system 49
4.4 Modes of liquid chromatography 57
4.5 High-throughput bioanalysis 64
4.6 Chiral HPLC 65
4.7 Future trends in HPLC 66
4.8 Bibliography 68
Chapter 5 Mass Spectrometry and Quantitative Bioanalysis 69
5.1 Introduction 69
5.2 The instruments 70
5.3 Analytical interfaces 70
5.4 Ionisation 73
5.5 Mass analysers 75
5.6 Use of MS in quantitative LC-MS 76
5.7 Developing an LC-MS assay method 77
5.8 Bibliography 89
Chapter 6 Immunoassay in Pharmacokinetic and Pharmacodynamic Bioanalysis 90
6.1 Summary 90
6.2 The role of immunoassay in drug discovery and development 91
6.3 Principles of immunoassay 92
6.4 Assay development 95
6.5 Production of reagent antibodies 95
6.6 Selection and production of label 96
6.7 Assay development and optimisation 98
6.8 Assay validation 99
6.9 Immunoassays developed in-house 100
6.10 Commercial kit immunoassay 102
6.11 Data handling 103
6.12 Automation 103
6.13 Biomarkers 105
6.14 Case study: determination of COX-2 selectivity in human blood 107
6.15 Biological drugs 108
6.16 References 112
Chapter 7 Pre-Clinical Pharmacokinetics 113
7.1 Introduction 113
7.2 Pharmacokinetic parameters 115
7.3 Bioavailability 115
7.4 Calculation of pharmacokinetic parameters 116
7.5 Parameter derivations 120
7.6 Study design and data handling in pre-clinical drug development 125
7.7 Application of PK in drug discovery 127
7.8 Interspecies scaling 129
7.9 References 131
Chapter 8 Pharmacokinetic/Pharmacodynamic Modelling in Pre-Clinical Drug Discovery 132
8.1 The importance of pharmacokinetic/pharmacodynamic modelling 132
8.2 Advantages of incorporating PK/PD modelling in the drug discovery process 133
8.3 PK/PD in the drug discovery process 134
8.4 Principles of PK/PD modelling 136
8.5 Summary 140
8.6 References 141
Chapter 9 Toxicokinetics 142
9.1 Introduction 142
9.2 Study design 143
9.3 PK parameters for toxicokinetic evaluation 146
9.4 Reporting 149
9.5 Application of toxicokinetic data 150
9.6 Toxicokinetic-toxicodynamic relationships 151
9.7 Dose- and time-dependencies 152
9.8 References 155
Chapter 10 Protein Binding in Plasma: A Case History of a Highly Protein-Bound Drug 156
10.1 Introduction 156
10.2 The protein binding equilibrium 157
10.3 Determinants of the unbound fraction 157
10.4 Principal plasma binding proteins 158
10.5 The importance of protein binding in drug development 162
10.6 Techniques for measurement: a brief review of the more popular techniques including advantages and disadvantages 166
10.7 GV150526A: a case history of a highly bound drug 168
10.8 References 175
Chapter 11 Isotope Drug Studies in Man 176
11.1 Radiolabelled studies in man 176
11.2 Which isotope? 181
11.3 Calculations 181
11.4 Accelerator mass spectrometry 186
11.5 Future of AMS 189
11.6 Stable isotope studies 190
11.7 Acknowledgements 190
11.8 References 190
Chapter 12 Whole Body Autoradiography 191
12.1 Introduction 191
12.2 Historical background 192
12.3 Methodology 192
12.4 Study design 193
12.5 Obtaining whole body sections 194
12.6 Imaging 195
12.7 Quantitative whole body autoradiography 196
12.8 Applications of quantitative whole body autoradiography 197
12.9 References 206
Chapter 13 Phase I Metabolism 208
13.1 Introduction 208
13.2 Cytochrome P450s 209
13.3 Monoamine oxidases (MAO) 215
13.4 Flavin monooxygenases (FMO) 216
13.5 Alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH) 218
13.6 Molybdenum hydroxylases 218
13.7 Conclusions 221
Chapter 14 Phase II Enzymes 222
14.1 Introduction 222
14.2 Phase II enzyme reactions 223
14.3 Nomenclature of phase II enzymes 232
14.4 Phase II enzymes and drug development 236
14.5 Summary 241
14.6 References 242
Chapter 15 In Vitro Techniques for Investigating Drug Metabolism 244
15.1 Introduction 244
15.2 Preparation of liver subcellular fractions and hepatocytes 247
15.3 Use of subcellular fractions, hepatocytes and liver slices to study drug metabolism 254
15.4 In vitro-in vivo correlations 256
15.5 Advantages and disadvantages of the in vitro systems used to study drug metabolism 258
15.6 The study of drug interactions using in vitro systems 261
15.7 References 266
Chapter 16 Drug-Drug Interactions: An in Vitro Approach 269
16.1 Introduction 269
16.2 Clinical background 270
16.3 The impetus behind an in vitro approach 270
16.4 The mechanism behind drug-drug interactions 271
16.5 Drug-metabolising enzymes 272
16.6 Drug transport systems 273
16.7 Plasma protein binding 274
16.8 Drug concentration effects 275
16.9 Inhibition of drug-metabolising enzymes and its effect 275
16.10 Induction of drug-metabolising enzymes and its effect 280
16.11 In vitro approaches to investigating drug interaction 281
16.12 A regulatory perspective 286
16.13 Some brief case histories 286
16.14 Overview 289
16.15 References 290
Chapter 17 Identification of Drug Metabolites in Biological Fluids Using Qualitative Spectroscopic and Chromatographic Techniques 292
17.1 Introduction 292
17.2 Mass spectrometry 293
17.3 Sample preparation 294
17.4 Phase I 295
17.5 Phase II 301
17.6 NMR spectroscopy 310
17.7 Characterisation of metabolites by [superscript 1]H NMR 314
17.8 [superscript 19]F NMR metabolite profiling 322
17.9 Conclusions 322
Chapter 18 Molecular Biology 325
18.1 Introduction 325
18.2 Basic molecular biology 325
18.3 Which enzyme? 329
18.4 Expressed enzymes 329
18.5 Induction or suppression? 341
18.6 Population genetics and polymorphisms 349
18.7 References 352
18.8 Bibliography 358
Chapter 19 The Role of Drug Metabolism and Pharmacokinetics in Drug Discovery: Past, Present and Future 359
19.1 Introduction 359
19.2 The first principle: potency versus efficacy 361
19.3 Which are the key kinetic parameters to measure? 363
19.4 Assessment of absorption and systemic availability 363
19.5 Cell-based models of absorption 367
19.6 The importance of clearance 368
19.7 Distribution and protein binding 371
19.8 Half-life and duration of action 372
19.9 Modifying structures to block metabolism 373
19.10 What do we do about inhibitors and inducers? 375
19.11 What does the ideal drug look like? 376
19.12 The future 377
19.13 Summary 379
19.14 References 379
Index 382