 Pharmacokinetics and Metabolism in Drug Design, 2nd Edition
ISBN: 978-3-527-31368-6
Hardcover
207 pages
May 2006
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Abbreviations and Symbols.
1. Physicochemistry.
1.1 Physicochemistry and Pharmacokinetics.
1.2 Partition and Distribution Coefficient as Measures of Lipophilicity.
1.3 Limitations on the Use of 1-Octanol.
1.4 Further Understanding of Log P.
1.4.1 Unravelling the Principal Contributions to Log P.
1.4.2 Hydrogen Bonding.
1.4.3 Molecular Size and Shape.
1.5 Alternative Lipophilicity Scales.
1.5.1 Different Solvent Systems.
1.5.2 Chromatographic Approaches.
1.5.3 Liposome Partitioning.
1.6 Computational Approaches to Lipophilicity.
1.7 Membrane Systems to Study Drug Behaviour.
1.8 Dissolution and Solubility.
1.8.1 Why Measure Solubility?
1.8.2 Calculated Solubility.
1.9 Ionisation (pKa).
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 Slow Offset Compounds.
2.12 Factors Governing Unbound Drug Concentration.
3. Absorption.
3.1 The Absorption Process.
3.2 Dissolution.
3.3 Membrane Transfer.
3.4 Barriers to Membrane Transfer.
3.5 Models for Absorption Estimation.
3.6 Estimation of Absorption Potential.
3.7 Computational Approaches.
4. Distribution.
4.1 Membrane Transfer Access to the Target.
4.2 Brain Penetration.
4.3 Volume of Distribution and Duration.
4.4 Distribution and T<sub>max</sub>.
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.
6. Renal Clearance.
6.1 Kidney Anatomy and Function.
6.2 Lipophilicity and Reabsorption bu 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.
7. Metabolic (Hepatic) Clearance.
7.1 Function of Metabolism (Biotransformation).
7.2 Cytochrome.
7.2.1 Catalytic Selectivity of CYP2D6.
7.2.2 Catalytic Selectivity of CYP2C9.
7.2.3 Catalytic Selectivity of CYP3A4.
7.3 Other Oxidative Metabolism Processes.
7.4 Oxidative Metabolism and Drug Design.
7.5 Non-Specific Esterases.
7.5.1 Function of Esterases.
7.5.2 Ester Drugs as Intravenous and Topical Agents.
7.6 Prodrugs to Aid Membrane Transfer.
7.7 Enzymes Catalysing Drug Conjugation.
7.7.1 Glucuronyl and Sulpho-Transferases.
7.7.2 Methyl Transferases.
7.7.3 Glutathione S-Transferases.
7.8 Stability to Conjugation Processes.
7.9 Pharmacodynamics and Conjugation.
8. Toxicity.
8.1 Toxicity Findings.
8.1.1 Pharmacophore-induced Toxicity.
8.1.2 Structure-related Toxicity.
8.1.3 Metabolism-induced Toxicity.
8.2 Importance of Dose Size.
8.3 Expoxides.
8.4 Quinone Imines.
8.5 Nitrenium Ions.
8.6 Iminium Ions.
8.7 Hydroxylamines.
8.8 Thiophene Rings.
8.9 Thioureas.
8.10 Chloroquinolines.
8.11 Stratification of Toxicity.
8.12 Toxicity Prediction: Computational Toxicology.
8.13 Toxicogenomics.
8.14 Enzyme Induction (CYP3A4) and Drug Design.
8.15 Enzyme Inhibition and Drug Design.
9. Inter-Species Scaling.
9.1 Objectives of Inter-Species Scaling.
9.2 Allometric Scaling.
9.2.1 Volume of Distribution.
9.2.2 Clearance.
9.3 Species Scaling: Adjusting for Maximum Life Span Potential.
9.4 Species Scaling: Incorporating Differences in Metabolic Clearance.
9.5 Inter-Species Scaling for Clearance by Hepatic Uptake.
9.6 Elimination Half-Life.
9.7 Scaling to Pharmacological Effect.
9.8 Single Animal Scaling.
10. High(er) throughput ADME Studies.
10.1 The High-Throughput Screening (HTS) Trend.
10.2 Drug Metabolism and Discovery Screening Sequences.
10.3 Physicochemistry.
10.3.1 Solubility.
10.3.2 Lipophilicity.
10.4 Absorption/Permeability.
10.5 Pharmacokinetics.
10.6 Metabolism and Inhibition.
10.7 The Concept of ADME Space.
10.8 Computational Approaches in PK and Metabolism.
10.8.1 QSPR and QSMR.
10.8.2 PK Predictions Using QSAR and Neural Networks.
10.8.3 Is In Silico Meeting Medicinal chemistry Needs in ADME Prediction?
10.8.4 Physiologically-Based Pharmacolinetic (PBPK) Modelling.
10.9 Outlook.
Index.
