Contributors.

1 Introduction (Corinne Kay).

1.1 Introduction.

1.2 Voyage Through The Digestive System.

1.3 The Liver Metabolism.

1.4 The Kidneys.

1.5 Conclusions.

2 In Silico ADME/Tox Predictions (David Lagorce, Christelle Reynes, Anne-Claude Camproux, Maria A. Miteva, Olivier Sperandio, and Bruno O. Villoutreix).

2.1 Introduction.

2.2 Key Computer Methods for ADME/Tox Predictions.

2.3 Preparation of Compound Collections and Computer Programs, Challenging ADME/Tox Predictions and Statistical Methods.

2.4 ADME/Tox Predictions within Pharmaceutics Companies.

2.5 Challenging ADME/Tox Predictions.

2.6 Statistical Methods.

2.7 Conclusions.

3 Absorption and Physicochemical Properties of the NCE (Jon Selbo and Po-Chang Chiang).

3.1. Introduction.

3.2. Physicochemical Properties.

3.3. Stability.

3.4. Dissolution and Solubility.

3.5. Solid State.

4 ADME (Martin E. Dowty, Dean M. Messing, Yurong Lai, and Leonid (Leo) Kirkovsky).

4.1 Introduction.

4.2 Absorption.

4.3 Distribution.

4.4 Elimination.

4.5 Drug Interactions.

4.6 Strategies for Assessing ADME Properties.

4.7 Tool Summary for Assessing ADME Properties.

5 Pharmacokinetics for Medicinal Chemists (Leonid (Leo) Kirkovsky and Anup Zutshi).

5.1 Introduction.

5.2 ADME.

5.3 The Mathematics of Pharmacokinetics.

5.4 Drug Administration and PK Observations.

5.5 Human PK Projection.

5.6 PK Practices.

5.7 Engineering Molecules with Desired ADME Profile.

6 Cardiac Toxicity (Ralf Kettenhofen and Silke Schwengberg).

6.1 Introduction.

6.2 Ion Channel-Related Cardiac Toxicity.

6.3 Nonarrhythmic Cardiac Toxicity.

7 Genetic Toxicity: In Vitro Approaches for Medicinal Chemists (Richard M. Walmsley and David Elder).

7.1 Introduction.

7.2 Limitations in the Regulatory In Vitro Genotoxicity Tests.

7.3 Practical Issues for Genotoxicity Profiling.

7.4 Computational Approaches to Genotoxicity Assessment: The In Silico Methods.

7.5 Genotoxicity Assays for Screening.

7.6 The "Omics".

7.7 Using Data from In Vitro Profiling: Confirmatory Tests, Follow-Up Tests, and the Link to Safety Assessment and In Vivo Models.

7.8 What to Test, When, and How.

7.9 Changes to Regulatory Guidelines Can Influence Screening Strategy.

7.10 Summary.

8 Hepatic Toxicity (Jinghai James Xu and Keith Hoffmaster).

8.1 Introduction.

8.2 Mechanisms of DILI.

8.3 Assays and Test Systems to Measure Various Types of DILI.

8.4 Medicinal Chemistry Strategies to Minimize DILI.

8.5 Future Outlooks.

9 In Vivo Toxicological Considerations (John P. Devine, Jr).

9.1 Introduction.

9.2 Route of Administration.

9.3 Formulation Issues.

9.4 Compound Requirements.

9.5 Animal Models.

9.6 IND-Supporting Toxicology Studies.

9.7 Study Result Interpretation.

9.8 Genetic Toxicology Studies.

9.9 Conclusion.

10 Preclinical Candidate Nomination and Development (Nils Bergenhem).

10.1 Introduction.

10.2 Investigational New Drug Application and Clinical Development.

10.3 Strategic Goals for the Preclinical Development.

10.4 Selection of Preclinical Development Candidate.

10.5 CMC.

10.6 Preclinical Studies.

10.7 Conclusions.

11 Fragment-Based Drug Design: Considerations for Good ADME Properties (Haitao Ji).

11.1 Introduction.

11.2 Fragment-Based Screening.

11.3 Case Studies of Fragment-Based Screening for Better Bioavailability.

11.4 De Novo Design.

11.5 Case Studies of De Novo Design for Better Bioavailability.

11.6 Minimal Pharmacophoric Elements and Fragment Hopping.

11.7 Conclusions and Future Perspectives.

Acknowledgments.

References.

Index.