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Full Description
In this new edition of a bestseller, all the contents have been brought upto-date by addressing current standards and best practices in the assessment and prediction of ADMET properties. Although the previous chapter layout has been retained, substantial revisions have been made, with new topics such as pro-drugs, active metabolites and transporters covered in detail in a manner useful to the Drug Discovery scientist. The authors discuss the parameters and processes important for the absorption, distribution and retention of drug compounds in the body, plus the potential problems created by their transformation into toxic byproducts.
While aimed at all those dealing professionally with the development and application of pharmaceutical substances, the readily comprehensible style makes this book equally suitable for students of pharmacy and related subjects. Uniquely comprehensive, the book relates physicochemistry and chemical structure to pharmacokinetic properties and ultimately drug efficacy and safety.
Contents
A Personal Foreword ix
1 Physicochemistry 1
1.1 Physicochemistry and Pharmacokinetics 2
1.2 Partition and Distribution Coefficients as Measures of Lipophilicity 2
1.3 Limitations on the Use of 1-Octanol 5
1.4 Further Understanding of log P 6
1.4.1 Unraveling the Principal Contributions to log P 6
1.4.2 Hydrogen Bonding 7
1.4.3 Polar Surface Area 8
1.4.4 Molecular Size and Shape 9
1.5 Alternative Lipophilicity Scales 10
1.6 Computational Systems to Determine Lipophilicity 10
1.7 Membrane Systems to Study Drug Behavior 10
1.8 Dissolution and Solubility 12
1.9 The BCS Classification and Central Role of Permeability 13
References 15
2 Pharmacokinetics 19
2.1 Setting the Scene 20
2.2 Intravenous Administration: Volume of Distribution 21
2.3 Intravenous Administration: Clearance 22
2.4 Intravenous Administration: Clearance and Half-life 23
2.5 Intravenous Administration: Infusion 24
2.6 Oral Administration 26
2.7 Repeated Doses 27
2.8 Development of the Unbound (Free) Drug Model 29
2.9 Unbound Drug and Drug Action 29
2.10 Unbound Drug Model and Barriers to Equilibrium 32
2.11 Pharmacodynamic Models 34
2.12 Slow Offset Compounds 35
2.13 Factors Governing Unbound Drug Concentration 38
References 40
3 Absorption 41
3.1 The Absorption Process 42
3.2 Dissolution 42
3.3 Membrane Transfer 44
3.4 Barriers to Membrane Transfer 49
3.5 Prodrugs to Increase Oral Absorption 51
3.6 Active Transport 55
3.7 Models for Absorption Estimation 56
3.8 Estimation of Absorption Potential and other Computational Approaches 56
References 57
4 Distribution 61
4.1 Membrane Transfer Access to the Target 62
4.2 Brain Penetration 63
4.2.1 Accumulation of Lower Permeability Compounds into the Brain 67
4.2.2 Distribution into Tumors 68
4.2.3 Volume of Distribution and Duration 70
4.2.4 Distribution and T max 77
References 78
5 Clearance 81
5.1 The Clearance Processes 82
5.2 Role of Transport Proteins in Drug Clearance 83
5.3 Interplay Between Metabolic and Renal Clearance 87
5.4 Role of Lipophilicity in Drug Clearance 87
5.5 Active Metabolites 88
5.6 Balancing the Rate of Renal and Metabolic clearance and Potency 91
References 101
6 Renal Clearance 103
6.1 Kidney Anatomy and Function 103
6.2 Lipophilicity and Reabsorption by the Kidney 105
6.3 Effect of Charge on Renal Clearance 106
6.4 Plasma Protein Binding and Renal Clearance 106
6.5 Balancing Renal Clearance and Absorption 108
6.6 Renal Clearance and Drug Design 109
References 110
7 Metabolic (Hepatic) Clearance 111
7.1 Symbols 111
7.2 Function of Metabolism (Biotransformation) 112
7.3 Cytochrome P 450 112
7.3.1 Catalytic Selectivity of CYP2D 6 115
7.3.2 Catalytic Selectivity of CYP2C 9 117
7.3.3 Catalytic Selectivity of CYP3A 4 119
7.4 Other Oxidative Metabolism Processes 126
7.4.1 Aldehyde Oxidase 126
7.4.2 Flavin-Containing Monooxygenases 130
7.4.3 Monoamine Oxidases 133
7.5 Oxidative Metabolism and Drug Design 138
7.6 Nonspecific Esterases 138
7.6.1 Function of Esterases 138
7.6.2 Ester Drugs as Intravenous and Topical Agents 140
7.7 Prodrugs to Aid Membrane Transfer 142
7.8 Enzymes Catalyzing Drug Conjugation 144
7.8.1 Glucuronosyl- and Sulfotransferases 144
7.8.2 Methyl Transferases 147
7.8.3 Glutathione-S-Transferases 148
7.9 Stability to Conjugation Processes 149
7.10 Pharmacodynamics and Conjugation 152
References 153
8 Toxicity 159
8.1 Toxicity Findings 160
8.1.1 Pharmacologic Mechanism-Based Toxicity 160
8.1.2 Chemotype-Dependent Toxicity 161
8.1.3 Metabolism-Induced Toxicity 164
8.2 Structure-Toxicity Analyses 167
8.3 Reactive Metabolite Screening in Drug Discovery 171
8.4 Structural Alerts/Toxicophores in Drug Design 173
8.5 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies - Effect of Daily Dose 173
8.6 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies - Competing Detoxication Pathways 182
8.7 Stratification of Toxicity 183
8.8 Toxicity Prediction: Computational Toxicology 183
8.9 Toxicogenomics 184
8.10 Pharmacogenomics 185
8.11 Enzyme Induction and Drug Design 186
8.12 Enzyme Inhibition and Drug Design 191
8.12.1 Quasi-Irreversible Inhibition 191
8.12.2 Irreversible CYP Inactivation via Apoprotein and/or Heme Covalent Modification 193
8.12.3 CYP Inhibition by Nitrogen-Containing Heterocycles 195
References 202
9 Predicting Human Pharmacokinetics 209
9.1 Objectives of Predicting Human Pharmacokinetics 210
9.2 Allometric Scaling of Preclinical In Vivo PK Parameters 211
9.2.1 Volume of Distribution 211
9.2.2 Clearance 214
9.3 Prediction of Human PK Parameters Using In Vitro Data 220
9.3.1 Predicting Human Volume of Distribution from In vitro Data 220
9.3.2 Predicting Human Clearance from Human In Vitro Data 222
9.3.3 Species Scaling: Incorporating Differences in Metabolic Clearance 223
9.4 Elimination Half-Life 224
9.5 Moving Forward 224
References 225
10 ADME Screening 229
10.1 The High-Throughput Synthesis and Screening Trend 230
10.2 The Concept of ADME Space 231
10.3 Drug Metabolism and Discovery Screening Sequences 233
10.4 Physicochemistry 234
10.4.1 Solubility 235
10.4.2 Ionization 236
10.4.3 Lipophilicity 236
10.4.4 Polar Surface Area 237
10.5 Absorption/Permeability 238
10.6 Metabolism, Induction, and Inhibition 239
10.7 Transporters 240
10.8 Protein Binding 242
10.9 Pharmacokinetics 243
10.10 In silico Approaches to ADME 243
10.10.1 QSAR Approaches to ADME 244
10.10.2 Theoretical Models for Predicting Metabolism 244
10.10.3 Physiologically-Based Pharmacokinetic Modeling 245
References 246
Index 251
