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 R & D 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 ) 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 (PDM) 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 Group (Groton 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. DonWalker 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 ix1 Physicochemistry 11.1 Physicochemistry and Pharmacokinetics 21.2 Partition and Distribution Coefficients as Measures of Lipophilicity 21.3 Limitations on the Use of 1-Octanol 51.4 Further Understanding of log P 61.4.1 Unraveling the Principal Contributions to log P 61.4.2 Hydrogen Bonding 71.4.3 Polar Surface Area 81.4.4 Molecular Size and Shape 91.5 Alternative Lipophilicity Scales 101.6 Computational Systems to Determine Lipophilicity 101.7 Membrane Systems to Study Drug Behavior 101.8 Dissolution and Solubility 121.9 The BCS Classification and Central Role of Permeability 13References 152 Pharmacokinetics 192.1 Setting the Scene 202.2 Intravenous Administration: Volume of Distribution 212.3 Intravenous Administration: Clearance 222.4 Intravenous Administration: Clearance and Half-life 232.5 Intravenous Administration: Infusion 242.6 Oral Administration 262.7 Repeated Doses 272.8 Development of the Unbound (Free) Drug Model 292.9 Unbound Drug and Drug Action 292.10 Unbound Drug Model and Barriers to Equilibrium 322.11 Pharmacodynamic Models 342.12 Slow Offset Compounds 352.13 Factors Governing Unbound Drug Concentration 38References 403 Absorption 413.1 The Absorption Process 423.2 Dissolution 423.3 Membrane Transfer 443.4 Barriers to Membrane Transfer 493.5 Prodrugs to Increase Oral Absorption 513.6 Active Transport 553.7 Models for Absorption Estimation 563.8 Estimation of Absorption Potential and other Computational Approaches 56References 574 Distribution 614.1 Membrane Transfer Access to the Target 624.2 Brain Penetration 634.2.1 Accumulation of Lower Permeability Compounds into the Brain 674.2.2 Distribution into Tumors 684.2.3 Volume of Distribution and Duration 704.2.4 Distribution and T max 77References 785 Clearance 815.1 The Clearance Processes 825.2 Role of Transport Proteins in Drug Clearance 835.3 Interplay Between Metabolic and Renal Clearance 875.4 Role of Lipophilicity in Drug Clearance 875.5 Active Metabolites 885.6 Balancing the Rate of Renal and Metabolic clearance and Potency 91References 1016 Renal Clearance 1036.1 Kidney Anatomy and Function 1036.2 Lipophilicity and Reabsorption by the Kidney 1056.3 Effect of Charge on Renal Clearance 1066.4 Plasma Protein Binding and Renal Clearance 1066.5 Balancing Renal Clearance and Absorption 1086.6 Renal Clearance and Drug Design 109References 1107 Metabolic (Hepatic) Clearance 1117.1 Symbols 1117.2 Function of Metabolism (Biotransformation) 1127.3 Cytochrome P 450 1127.3.1 Catalytic Selectivity of CYP2D 6 1157.3.2 Catalytic Selectivity of CYP2C 9 1177.3.3 Catalytic Selectivity of CYP3A 4 1197.4 Other Oxidative Metabolism Processes 1267.4.1 Aldehyde Oxidase 1267.4.2 Flavin-Containing Monooxygenases 1307.4.3 Monoamine Oxidases 1337.5 Oxidative Metabolism and Drug Design 1387.6 Nonspecific Esterases 1387.6.1 Function of Esterases 1387.6.2 Ester Drugs as Intravenous and Topical Agents 1407.7 Prodrugs to Aid Membrane Transfer 1427.8 Enzymes Catalyzing Drug Conjugation 1447.8.1 Glucuronosyl- and Sulfotransferases 1447.8.2 Methyl Transferases 1477.8.3 Glutathione-S-Transferases 1487.9 Stability to Conjugation Processes 1497.10 Pharmacodynamics and Conjugation 152References 1538 Toxicity 1598.1 Toxicity Findings 1608.1.1 Pharmacologic Mechanism-Based Toxicity 1608.1.2 Chemotype-Dependent Toxicity 1618.1.3 Metabolism-Induced Toxicity 1648.2 Structure–Toxicity Analyses 1678.3 Reactive Metabolite Screening in Drug Discovery 1718.4 Structural Alerts/Toxicophores in Drug Design 1738.5 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies – Effect of Daily Dose 1738.6 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies – Competing Detoxication Pathways 1828.7 Stratification of Toxicity 1838.8 Toxicity Prediction: Computational Toxicology 1838.9 Toxicogenomics 1848.10 Pharmacogenomics 1858.11 Enzyme Induction and Drug Design 1868.12 Enzyme Inhibition and Drug Design 1918.12.1 Quasi-Irreversible Inhibition 1918.12.2 Irreversible CYP Inactivation via Apoprotein and/or Heme Covalent Modification 1938.12.3 CYP Inhibition by Nitrogen-Containing Heterocycles 195References 2029 Predicting Human Pharmacokinetics 2099.1 Objectives of Predicting Human Pharmacokinetics 2109.2 Allometric Scaling of Preclinical In Vivo PK Parameters 2119.2.1 Volume of Distribution 2119.2.2 Clearance 2149.3 Prediction of Human PK Parameters Using In Vitro Data 2209.3.1 Predicting Human Volume of Distribution from In vitro Data 2209.3.2 Predicting Human Clearance from Human In Vitro Data 2229.3.3 Species Scaling: Incorporating Differences in Metabolic Clearance 2239.4 Elimination Half-Life 2249.5 Moving Forward 224References 22510 ADME Screening 22910.1 The High-Throughput Synthesis and Screening Trend 23010.2 The Concept of ADME Space 23110.3 Drug Metabolism and Discovery Screening Sequences 23310.4 Physicochemistry 23410.4.1 Solubility 23510.4.2 Ionization 23610.4.3 Lipophilicity 23610.4.4 Polar Surface Area 23710.5 Absorption/Permeability 23810.6 Metabolism, Induction, and Inhibition 23910.7 Transporters 24010.8 Protein Binding 24210.9 Pharmacokinetics 24310.10 In silico Approaches to ADME 24310.10.1 QSAR Approaches to ADME 24410.10.2 Theoretical Models for Predicting Metabolism 24410.10.3 Physiologically-Based Pharmacokinetic Modeling 245References 246Index 251

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 R & D 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 ) 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 (PDM) 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 Group (Groton 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. DonWalker 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 ix1 Physicochemistry 11.1 Physicochemistry and Pharmacokinetics 21.2 Partition and Distribution Coefficients as Measures of Lipophilicity 21.3 Limitations on the Use of 1-Octanol 51.4 Further Understanding of log P 61.4.1 Unraveling the Principal Contributions to log P 61.4.2 Hydrogen Bonding 71.4.3 Polar Surface Area 81.4.4 Molecular Size and Shape 91.5 Alternative Lipophilicity Scales 101.6 Computational Systems to Determine Lipophilicity 101.7 Membrane Systems to Study Drug Behavior 101.8 Dissolution and Solubility 121.9 The BCS Classification and Central Role of Permeability 13References 152 Pharmacokinetics 192.1 Setting the Scene 202.2 Intravenous Administration: Volume of Distribution 212.3 Intravenous Administration: Clearance 222.4 Intravenous Administration: Clearance and Half-life 232.5 Intravenous Administration: Infusion 242.6 Oral Administration 262.7 Repeated Doses 272.8 Development of the Unbound (Free) Drug Model 292.9 Unbound Drug and Drug Action 292.10 Unbound Drug Model and Barriers to Equilibrium 322.11 Pharmacodynamic Models 342.12 Slow Offset Compounds 352.13 Factors Governing Unbound Drug Concentration 38References 403 Absorption 413.1 The Absorption Process 423.2 Dissolution 423.3 Membrane Transfer 443.4 Barriers to Membrane Transfer 493.5 Prodrugs to Increase Oral Absorption 513.6 Active Transport 553.7 Models for Absorption Estimation 563.8 Estimation of Absorption Potential and other Computational Approaches 56References 574 Distribution 614.1 Membrane Transfer Access to the Target 624.2 Brain Penetration 634.2.1 Accumulation of Lower Permeability Compounds into the Brain 674.2.2 Distribution into Tumors 684.2.3 Volume of Distribution and Duration 704.2.4 Distribution and T max 77References 785 Clearance 815.1 The Clearance Processes 825.2 Role of Transport Proteins in Drug Clearance 835.3 Interplay Between Metabolic and Renal Clearance 875.4 Role of Lipophilicity in Drug Clearance 875.5 Active Metabolites 885.6 Balancing the Rate of Renal and Metabolic clearance and Potency 91References 1016 Renal Clearance 1036.1 Kidney Anatomy and Function 1036.2 Lipophilicity and Reabsorption by the Kidney 1056.3 Effect of Charge on Renal Clearance 1066.4 Plasma Protein Binding and Renal Clearance 1066.5 Balancing Renal Clearance and Absorption 1086.6 Renal Clearance and Drug Design 109References 1107 Metabolic (Hepatic) Clearance 1117.1 Symbols 1117.2 Function of Metabolism (Biotransformation) 1127.3 Cytochrome P 450 1127.3.1 Catalytic Selectivity of CYP2D 6 1157.3.2 Catalytic Selectivity of CYP2C 9 1177.3.3 Catalytic Selectivity of CYP3A 4 1197.4 Other Oxidative Metabolism Processes 1267.4.1 Aldehyde Oxidase 1267.4.2 Flavin-Containing Monooxygenases 1307.4.3 Monoamine Oxidases 1337.5 Oxidative Metabolism and Drug Design 1387.6 Nonspecific Esterases 1387.6.1 Function of Esterases 1387.6.2 Ester Drugs as Intravenous and Topical Agents 1407.7 Prodrugs to Aid Membrane Transfer 1427.8 Enzymes Catalyzing Drug Conjugation 1447.8.1 Glucuronosyl- and Sulfotransferases 1447.8.2 Methyl Transferases 1477.8.3 Glutathione-S-Transferases 1487.9 Stability to Conjugation Processes 1497.10 Pharmacodynamics and Conjugation 152References 1538 Toxicity 1598.1 Toxicity Findings 1608.1.1 Pharmacologic Mechanism-Based Toxicity 1608.1.2 Chemotype-Dependent Toxicity 1618.1.3 Metabolism-Induced Toxicity 1648.2 Structure–Toxicity Analyses 1678.3 Reactive Metabolite Screening in Drug Discovery 1718.4 Structural Alerts/Toxicophores in Drug Design 1738.5 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies – Effect of Daily Dose 1738.6 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies – Competing Detoxication Pathways 1828.7 Stratification of Toxicity 1838.8 Toxicity Prediction: Computational Toxicology 1838.9 Toxicogenomics 1848.10 Pharmacogenomics 1858.11 Enzyme Induction and Drug Design 1868.12 Enzyme Inhibition and Drug Design 1918.12.1 Quasi-Irreversible Inhibition 1918.12.2 Irreversible CYP Inactivation via Apoprotein and/or Heme Covalent Modification 1938.12.3 CYP Inhibition by Nitrogen-Containing Heterocycles 195References 2029 Predicting Human Pharmacokinetics 2099.1 Objectives of Predicting Human Pharmacokinetics 2109.2 Allometric Scaling of Preclinical In Vivo PK Parameters 2119.2.1 Volume of Distribution 2119.2.2 Clearance 2149.3 Prediction of Human PK Parameters Using In Vitro Data 2209.3.1 Predicting Human Volume of Distribution from In vitro Data 2209.3.2 Predicting Human Clearance from Human In Vitro Data 2229.3.3 Species Scaling: Incorporating Differences in Metabolic Clearance 2239.4 Elimination Half-Life 2249.5 Moving Forward 224References 22510 ADME Screening 22910.1 The High-Throughput Synthesis and Screening Trend 23010.2 The Concept of ADME Space 23110.3 Drug Metabolism and Discovery Screening Sequences 23310.4 Physicochemistry 23410.4.1 Solubility 23510.4.2 Ionization 23610.4.3 Lipophilicity 23610.4.4 Polar Surface Area 23710.5 Absorption/Permeability 23810.6 Metabolism, Induction, and Inhibition 23910.7 Transporters 24010.8 Protein Binding 24210.9 Pharmacokinetics 24310.10 In silico Approaches to ADME 24310.10.1 QSAR Approaches to ADME 24410.10.2 Theoretical Models for Predicting Metabolism 24410.10.3 Physiologically-Based Pharmacokinetic Modeling 245References 246Index 251

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 R & D 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 ) 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 (PDM) 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 Group (Groton 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. DonWalker 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 ix1 Physicochemistry 11.1 Physicochemistry and Pharmacokinetics 21.2 Partition and Distribution Coefficients as Measures of Lipophilicity 21.3 Limitations on the Use of 1-Octanol 51.4 Further Understanding of log P 61.4.1 Unraveling the Principal Contributions to log P 61.4.2 Hydrogen Bonding 71.4.3 Polar Surface Area 81.4.4 Molecular Size and Shape 91.5 Alternative Lipophilicity Scales 101.6 Computational Systems to Determine Lipophilicity 101.7 Membrane Systems to Study Drug Behavior 101.8 Dissolution and Solubility 121.9 The BCS Classification and Central Role of Permeability 13References 152 Pharmacokinetics 192.1 Setting the Scene 202.2 Intravenous Administration: Volume of Distribution 212.3 Intravenous Administration: Clearance 222.4 Intravenous Administration: Clearance and Half-life 232.5 Intravenous Administration: Infusion 242.6 Oral Administration 262.7 Repeated Doses 272.8 Development of the Unbound (Free) Drug Model 292.9 Unbound Drug and Drug Action 292.10 Unbound Drug Model and Barriers to Equilibrium 322.11 Pharmacodynamic Models 342.12 Slow Offset Compounds 352.13 Factors Governing Unbound Drug Concentration 38References 403 Absorption 413.1 The Absorption Process 423.2 Dissolution 423.3 Membrane Transfer 443.4 Barriers to Membrane Transfer 493.5 Prodrugs to Increase Oral Absorption 513.6 Active Transport 553.7 Models for Absorption Estimation 563.8 Estimation of Absorption Potential and other Computational Approaches 56References 574 Distribution 614.1 Membrane Transfer Access to the Target 624.2 Brain Penetration 634.2.1 Accumulation of Lower Permeability Compounds into the Brain 674.2.2 Distribution into Tumors 684.2.3 Volume of Distribution and Duration 704.2.4 Distribution and T max 77References 785 Clearance 815.1 The Clearance Processes 825.2 Role of Transport Proteins in Drug Clearance 835.3 Interplay Between Metabolic and Renal Clearance 875.4 Role of Lipophilicity in Drug Clearance 875.5 Active Metabolites 885.6 Balancing the Rate of Renal and Metabolic clearance and Potency 91References 1016 Renal Clearance 1036.1 Kidney Anatomy and Function 1036.2 Lipophilicity and Reabsorption by the Kidney 1056.3 Effect of Charge on Renal Clearance 1066.4 Plasma Protein Binding and Renal Clearance 1066.5 Balancing Renal Clearance and Absorption 1086.6 Renal Clearance and Drug Design 109References 1107 Metabolic (Hepatic) Clearance 1117.1 Symbols 1117.2 Function of Metabolism (Biotransformation) 1127.3 Cytochrome P 450 1127.3.1 Catalytic Selectivity of CYP2D 6 1157.3.2 Catalytic Selectivity of CYP2C 9 1177.3.3 Catalytic Selectivity of CYP3A 4 1197.4 Other Oxidative Metabolism Processes 1267.4.1 Aldehyde Oxidase 1267.4.2 Flavin-Containing Monooxygenases 1307.4.3 Monoamine Oxidases 1337.5 Oxidative Metabolism and Drug Design 1387.6 Nonspecific Esterases 1387.6.1 Function of Esterases 1387.6.2 Ester Drugs as Intravenous and Topical Agents 1407.7 Prodrugs to Aid Membrane Transfer 1427.8 Enzymes Catalyzing Drug Conjugation 1447.8.1 Glucuronosyl- and Sulfotransferases 1447.8.2 Methyl Transferases 1477.8.3 Glutathione-S-Transferases 1487.9 Stability to Conjugation Processes 1497.10 Pharmacodynamics and Conjugation 152References 1538 Toxicity 1598.1 Toxicity Findings 1608.1.1 Pharmacologic Mechanism-Based Toxicity 1608.1.2 Chemotype-Dependent Toxicity 1618.1.3 Metabolism-Induced Toxicity 1648.2 Structure–Toxicity Analyses 1678.3 Reactive Metabolite Screening in Drug Discovery 1718.4 Structural Alerts/Toxicophores in Drug Design 1738.5 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies – Effect of Daily Dose 1738.6 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies – Competing Detoxication Pathways 1828.7 Stratification of Toxicity 1838.8 Toxicity Prediction: Computational Toxicology 1838.9 Toxicogenomics 1848.10 Pharmacogenomics 1858.11 Enzyme Induction and Drug Design 1868.12 Enzyme Inhibition and Drug Design 1918.12.1 Quasi-Irreversible Inhibition 1918.12.2 Irreversible CYP Inactivation via Apoprotein and/or Heme Covalent Modification 1938.12.3 CYP Inhibition by Nitrogen-Containing Heterocycles 195References 2029 Predicting Human Pharmacokinetics 2099.1 Objectives of Predicting Human Pharmacokinetics 2109.2 Allometric Scaling of Preclinical In Vivo PK Parameters 2119.2.1 Volume of Distribution 2119.2.2 Clearance 2149.3 Prediction of Human PK Parameters Using In Vitro Data 2209.3.1 Predicting Human Volume of Distribution from In vitro Data 2209.3.2 Predicting Human Clearance from Human In Vitro Data 2229.3.3 Species Scaling: Incorporating Differences in Metabolic Clearance 2239.4 Elimination Half-Life 2249.5 Moving Forward 224References 22510 ADME Screening 22910.1 The High-Throughput Synthesis and Screening Trend 23010.2 The Concept of ADME Space 23110.3 Drug Metabolism and Discovery Screening Sequences 23310.4 Physicochemistry 23410.4.1 Solubility 23510.4.2 Ionization 23610.4.3 Lipophilicity 23610.4.4 Polar Surface Area 23710.5 Absorption/Permeability 23810.6 Metabolism, Induction, and Inhibition 23910.7 Transporters 24010.8 Protein Binding 24210.9 Pharmacokinetics 24310.10 In silico Approaches to ADME 24310.10.1 QSAR Approaches to ADME 24410.10.2 Theoretical Models for Predicting Metabolism 24410.10.3 Physiologically-Based Pharmacokinetic Modeling 245References 246Index 251