What is included with this book?
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 Tmax | 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 |
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