9783527329540

In this new edition of a bestseller, all the contents have been brought up-to-date by addressing current standards and best practices in the assessment and prediction of ADMET properties. New chapters on prodrugs, antitumor drugs and active metabolites, among other topics, have been added. The authors, all of them employed at Pfizer in the discovery and development of new active substances, 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. They cover everything from the fundamental principles right up to the impact of pharmacokinetic parameters on the discovery of new drugs. 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.

Dennis Smith worked in the pharmaceutical industry for more than 30 years since gaining his PhD from the University of Manchester (UK). He worked at Pfizer Global RD at Sandwich for 24 years, with the role of Vice President for Pharmacokinetics, Dynamics and Metabolism. During his career he directly contributed to the Discovery and Development of eight NCEs. Now retired he is still active in an academic (Visiting Professor, University of Liverpool; Honary Professor, University of Capetown) and in an advisory capacity. His research interests and publications span all aspects of drug discovery and development, particularly where drug metabolism impacts on the design of more efficacious and safer drugs. Charlotte Allerton obtained her first degree in chemistry from the University of Nottingham, and a MPhil in organic chemistry from the University of Cambridge. She joined the Medicinal Chemistry department in Pfizer at Sandwich in 1993 and worked across a range of disease areas, before joining the Pharmacokinetics, Dynamics and Metabolism (POM) department in 2007. In 2008 Charlotte Allerton became the PDM Sandwich Site Lead. Amit Kalgutkar received his PhD in organic chemistry from Virginia Polytechnic Institute (USA) and conducted a post-doctoral fellowship at the Department of Biochemistry, Vanderbilt University School of Medicine. He Joined Pfizer in 1999, where he is currently a Research Fellow in the Drug Metabolism Croup (Croton Laboratories). He is also an adjunct Professor in the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island. Han van de Waterbeemd studied physical organic chemistry at the Technical 'University of Eindhoven and did a PhD in medicinal chemistry at the University of Leiden, The Netherlands. In his pharmaceutical career he worked for Roche, Pfizer and AstraZeneca. His research interests include the role of molecular properties in drug disposition and computational modeling of ADMET properties. Don Walker obtained a degree in biochemistry from the University of London (UK). He worked for Pfizer for 24 years in the Pharmacokinetics, Dynamics and Metabolism Department contributing scientific leadership to the drug metabolism and pharmacokinetic evaluations on many drug discovery and development projects across a range of therapeutic areas including cardiovascular, allergy and respiratory, anti-infectives and sexual health. Following his retirement in 2010 he has continued to provide occasional consulting and lecturing in the field of metabolism and pharmacokinetics.

A Personal Foreword	p. ix
Physicochemistry	p. 1
Physicochemistry and PharmacoMnetics	p. 2
Partition and Distribution Coefficients as Measures of Iipophilicity	p. 2
limitations on the Use of 1-Octanol	p. 5
Further Understanding of log P	p. 6
Unraveling the Principal Contributions to log P	p. 6
Hydrogen Bonding	p. 7
Polar Surface Area	p. 8
Molecular Size and Shape	p. 9
Alternative Lipophilicity Scales	p. 10
Computational Systems to Determine Iipophilicity	p. 10
Membrane Systems to Study Drug Behavior	p. 10
Dissolution and Solubility	p. 12
The BCS Classification and Central Role of Permeability	p. 13
References	p. 15
Pharmacokinetics	p. 19
Setting the Scene	p. 20
Intravenous Administration: Volume of Distribution	p. 21
Intravenous Administration: Clearance	p. 22
Intravenous Administration: Clearance and Half-life	p. 23
Intravenous Administration: Infusion	p. 24
Oral Administration	p. 26
Repeated Doses	p. 27
Development of the Unbound (Free) Drug Model	p. 29
Unbound Drug and Drug Action	p. 29
Unbound Drug Model and Barriers to Equilibrium	p. 32
Pharmacodynamic Models	p. 34
Slow Offset Compounds	p. 35
Factors Governing Unbound Drug Concentration	p. 38
References	p. 40
Absorption	p. 41
The Absorption Process	p. 42
Dissolution	p. 42
Membrane Transfer	p. 44
Barriers to Membrane Transfer	p. 49
Prodrugs to Increase Oral Absorption	p. 51
Active Transport	p. 55
Models for Absorption Estimation	p. 56
Estimation of Absorption Potential and other Computational Approaches	p. 56
References	p. 57
Distribution	p. 61
Membrane Transfer Access to the Target	p. 62
Brain Penetration	p. 63
Accumulation of Lower Permeability Compounds into the Brain	p. 67
Distribution into Tumors	p. 68
Volume of Distribution and Duration	p. 70
Distribution and T_max	p. 77
References	p. 78
Clearance	p. 81
The Clearance Processes	p. 82
Role of Transport Proteins in Drug Clearance	p. 83
Interplay Between Metabolic and Renal Clearance	p. 87
Role of Lipophilicity in Drug Clearance	p. 87
Active Metabolites	p. 88
Balancing the Rate of Renal and Metabolic clearance and Potency	p. 91
References	p. 101
Renal Clearance	p. 103
Kidney Anatomy and Function	p. 103
Lipophilicity and Reabsorption by the Kidney	p. 105
Effect of Charge on Renal Clearance	p. 106
Plasma Protein Binding and Renal Clearance	p. 106
Balancing Renal Clearance and Absorption	p. 108
Renal Clearance and Drug Design	p. 209
References	p. 110
Metabolic (Hepatic) Clearance	p. 111
Symbols	p. 111
Function of Metabolism (Biotransformation)	p. 112
Cytochrome P450	p. 112
Catalytic Selectivity of CYP2D6	p. 115
Catalytic Selectivity of CYP2C9	p. 117
Catalytic Selectivity of CYP3A4	p. 119
Other Oxidative Metabolism Processes	p. 126
Aldehyde Oxidase	p. 126
Flavm-Containing Monooxygenases	p. 130
Monoarnine Oxidases	p. 133
Oxidative Metabolism and Drug Design	p. 138
Nonspecific Esterases	p. 138
Function of Esterases	p. 138
Ester Drugs as Intravenous and Topical Agents	p. 140
Prodrugs to Aid Membrane Transfer	p. 142
Enzymes Catalyzing Drug Conjugation	p. 144
Glucuronosyl- and Sulfotransferases	p. 144
Methyl Transferases	p. 147
Glutatbione-S-Transferases	p. 148
Stability to Conjugation Processes	p. 149
Pharmacodynamics and Conjugation	p. 152
References	p. 153
Toxicity	p. 159
Toxicity Findings	p. 160
Pharmacologic Mechanism-Based Toxicity	p. 160
Chemotype-Dependent Toxicity	p. 161
Metabolism-Induced Toxicity	p. 164
Structure-Toxicity Analyses	p. 167
Reactive Metabolite Screening in Drug Discovery	p. 171
Structural Alerts/Toxicophores in Drug Design	p. 173
Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies - Effect of Daily Dose	p. 173
Dealing with Reactive Metabolite Positives in Drug Discovery Risk Assessment Strategies - Competing Detoxication Pathways	p. 182
Stratification of Toxicity	p. 183
Toxicity Prediction: Computational Toxicology	p. 183
Toxicogenomics	p. 184
Pharrnacogenomics	p. 185
Enzyme Induction and Drug Design	p. 186
Enzyme Inhibition and Drug Design	p. 191
Quasi-Irreversible Inhibition	p. 191
Irreversible CYP Inactivation via Apoprotein and/or Heme Covalent Modification	p. 193
CYP Inhibition by Nitrogen-Containing Heterocycles	p. 195
References	p. 202
Predicting Human Pharmacokinetics	p. 209
Objectives of Predicting Human Pharmacokinetics	p. 210
Allometric Scaling of Predinical In Vivo PK Parameters	p. 211
Volume of Distribution	p. 211
Clearance	p. 214
Prediction of Human PK Parameters Using In Vitro Data	p. 220
Predicting Human Volume of Distribution from In vitro Data	p. 220
Predicting .Human Clearance from Human In Vitro Data	p. 222
Spedes Scaling: Incorporating Differences in Metabolic Clearance	p. 223
Elimination Half-life	p. 224
Moving Forward	p. 224
References	p. 225
ADME Screening	p. 229
The High-Throughput Synthesis and Screening Trend	p. 230
The Concept of ADME Space	p. 231
Drug Metabolism and Discovery Screening Sequences	p. 233
Physicochemistry	p. 234
Solubility	p. 235
Ionization	p. 236
Lipophilidty	p. 236
Polar Surface Area	p. 237
Absorption/Permeability	p. 238
Metabolism, Induction, and Inhibition	p. 239
Transporters	p. 240
Protein Binding	p. 242
Pharmacokinetics	p. 243
In silico Approaches to ADME	p. 243
QSAR Approaches to ADME	p. 244
Theoretical Models for Predicting Metabolism	p. 244
Physiologically-Based Pharmacokinetic Modeling	p. 245
References	p. 246
Index	p. 251
Table of Contents provided by Ingram. All Rights Reserved.

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Pharmacokinetics and Metabolism in Drug Design

Pharmacokinetics and Metabolism in Drug Design

3527329544

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