Pharmacokinetics and Metabolism in Drug Design -- Contents -- A Personal Foreword -- 1 Physicochemistry -- 1.1 Physicochemistry and Pharmacokinetics -- 1.2 Partition and Distribution Coefficients as Measures of Lipophilicity -- 1.3 Limitations on the Use of 1-Octanol -- 1.4 Further Understanding of log P -- 1.4.1 Unraveling the Principal Contributions to log P -- 1.4.2 Hydrogen Bonding -- 1.4.3 Polar Surface Area -- 1.4.4 Molecular Size and Shape -- 1.5 Alternative Lipophilicity Scales -- 1.6 Computational Systems to Determine Lipophilicity -- 1.7 Membrane Systems to Study Drug Behavior -- 1.8 Dissolution and Solubility -- 1.9 The BCS Classification and Central Role of Permeability -- References -- 2 Pharmacokinetics -- 2.1 Setting the Scene -- 2.2 Intravenous Administration: Volume of Distribution -- 2.3 Intravenous Administration: Clearance -- 2.4 Intravenous Administration: Clearance and Half-life -- 2.5 Intravenous Administration: Infusion -- 2.6 Oral Administration -- 2.7 Repeated Doses -- 2.8 Development of the Unbound (Free) Drug Model -- 2.9 Unbound Drug and Drug Action -- 2.10 Unbound Drug Model and Barriers to Equilibrium -- 2.11 Pharmacodynamic Models -- 2.12 Slow Offset Compounds -- 2.13 Factors Governing Unbound Drug Concentration -- References -- 3 Absorption -- 3.1 The Absorption Process -- 3.2 Dissolution -- 3.3 Membrane Transfer -- 3.4 Barriers to Membrane Transfer -- 3.5 Prodrugs to Increase Oral Absorption -- 3.6 Active Transport -- 3.7 Models for Absorption Estimation -- 3.8 Estimation of Absorption Potential and other Computational Approaches -- References -- 4 Distribution -- 4.1 Membrane Transfer Access to the Target -- 4.2 Brain Penetration -- 4.2.1 Accumulation of Lower Permeability Compounds into the Brain -- 4.2.2 Distribution into Tumors -- 4.2.3 Volume of Distribution and Duration -- 4.2.4 Distribution and Tmax.

References -- 5 Clearance -- 5.1 The Clearance Processes -- 5.2 Role of Transport Proteins in Drug Clearance -- 5.3 Interplay Between Metabolic and Renal Clearance -- 5.4 Role of Lipophilicity in Drug Clearance -- 5.5 Active Metabolites -- 5.6 Balancing the Rate of Renal and Metabolic clearance and Potency -- References -- 6 Renal Clearance -- 6.1 Kidney Anatomy and Function -- 6.2 Lipophilicity and Reabsorption by the Kidney -- 6.3 Effect of Charge on Renal Clearance -- 6.4 Plasma Protein Binding and Renal Clearance -- 6.5 Balancing Renal Clearance and Absorption -- 6.6 Renal Clearance and Drug Design -- References -- 7 Metabolic (Hepatic) Clearance -- 7.1 Symbols -- 7.2 Function of Metabolism (Biotransformation) -- 7.3 Cytochrome P450 -- 7.3.1 Catalytic Selectivity of CYP2D6 -- 7.3.2 Catalytic Selectivity of CYP2C9 -- 7.3.3 Catalytic Selectivity of CYP3A4 -- 7.4 Other Oxidative Metabolism Processes -- 7.4.1 Aldehyde Oxidase -- 7.4.2 Flavin-Containing Monooxygenases -- 7.4.3 Monoamine Oxidases -- 7.5 Oxidative Metabolism and Drug Design -- 7.6 Nonspecific Esterases -- 7.6.1 Function of Esterases -- 7.6.2 Ester Drugs as Intravenous and Topical Agents -- 7.7 Prodrugs to Aid Membrane Transfer -- 7.8 Enzymes Catalyzing Drug Conjugation -- 7.8.1 Glucuronosyl- and Sulfotransferases -- 7.8.2 Methyl Transferases -- 7.8.3 Glutathione-S-Transferases -- 7.9 Stability to Conjugation Processes -- 7.10 Pharmacodynamics and Conjugation -- References -- 8 Toxicity -- 8.1 Toxicity Findings -- 8.1.1 Pharmacologic Mechanism-Based Toxicity -- 8.1.2 Chemotype-Dependent Toxicity -- 8.1.3 Metabolism-Induced Toxicity -- 8.2 Structure-Toxicity Analyses -- 8.3 Reactive Metabolite Screening in Drug Discovery -- 8.4 Structural Alerts/Toxicophores in Drug Design.

8.5 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies - Effect of Daily Dose -- 8.6 Dealing with Reactive Metabolite Positives in Drug Discovery: Risk Assessment Strategies - Competing Detoxication Pathways -- 8.7 Stratification of Toxicity -- 8.8 Toxicity Prediction: Computational Toxicology -- 8.9 Toxicogenomics -- 8.10 Pharmacogenomics -- 8.11 Enzyme Induction and Drug Design -- 8.12 Enzyme Inhibition and Drug Design -- 8.12.1 Quasi-Irreversible Inhibition -- 8.12.2 Irreversible CYP Inactivation via Apoprotein and/or Heme Covalent Modification -- 8.12.3 CYP Inhibition by Nitrogen-Containing Heterocycles -- References -- 9 Predicting Human Pharmacokinetics -- 9.1 Objectives of Predicting Human Pharmacokinetics -- 9.2 Allometric Scaling of Preclinical In Vivo PK Parameters -- 9.2.1 Volume of Distribution -- 9.2.2 Clearance -- 9.3 Prediction of Human PK Parameters Using In Vitro Data -- 9.3.1 Predicting Human Volume of Distribution from In vitro Data -- 9.3.2 Predicting Human Clearance from Human In Vitro Data -- 9.3.3 Species Scaling: Incorporating Differences in Metabolic Clearance -- 9.4 Elimination Half-Life -- 9.5 Moving Forward -- References -- 10 ADME Screening -- 10.1 The High-Throughput Synthesis and Screening Trend -- 10.2 The Concept of ADME Space -- 10.3 Drug Metabolism and Discovery Screening Sequences -- 10.4 Physicochemistry -- 10.4.1 Solubility -- 10.4.2 Ionization -- 10.4.3 Lipophilicity -- 10.4.4 Polar Surface Area -- 10.5 Absorption/Permeability -- 10.6 Metabolism, Induction, and Inhibition -- 10.7 Transporters -- 10.8 Protein Binding -- 10.9 Pharmacokinetics -- 10.10 In silico Approaches to ADME -- 10.10.1 QSAR Approaches to ADME -- 10.10.2 Theoretical Models for Predicting Metabolism -- 10.10.3 Physiologically-Based Pharmacokinetic Modeling -- References -- Index.