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Pharmacokinetics and Metabolism in Drug Design, 2nd Edition




In this new edition of a bestseller, all the contents have been updated and new material has been added, especially in the areas of toxicity testing and high throughput analysis. The authors, all of them employed at Pfizer in the discovery and development of new active substances, discuss the significant 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.

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.


The second edition features several new subchapters on novel aspects or on fields that have received fresh attention by pharmaceutical scientists.
In the Physiochemistry chapter, new sections on compound solubility and ionisation have been added. Toxicity testing in animals has been expanded to cover single animal studies, and the recently evolved concept of ADME space is now introduced in the section on high throughput studies, where most of the subchapters have been rewritten and expanded.
Data in figures and tables have been updated where appropriate, and new references have been added.
"This work will interest and inform both the beginning professional in the field of drug discovery/design and the medicinal chemist…I also highly recommend it for students…" (Journal of Medicinal Chemistry, December 14, 2006)

"…extremely useful to students of Toxicology and others with an interest in the subject." (British Toxicology Society Newsletter, Summer 2007)