Pharmacokinetics and Metabolism in Drug Design Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H.Timmerman

Pharmacokinetics and Metabolism in Drug Design

Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)

Pharmacokinetics and Metabolism in Drug Design

by Dennis A. Smith,

Han van de Waterbeemd and Don K. Walker

Pharmacokinetics and Metabolism in Drug Design V

Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)

Contents

Preface IX

A Personal Foreword XI

1Physicochemistry 1

1.4.2Hydrogen Bonding 6

2Pharmacokinetics 15

2.6Oral Administration 22

2.7Repeated Doses 23

VI Contents

3Absorption 35

3.2Dissolution 36

3.3Membrane Transfer 37

3.7Computational Approaches 45

References 46

4Distribution 47

4.2Brain Penetration 48

5Clearance 59

6Renal Clearance 67

7.2Cytochrome P450 76

7.4Non-Specific Esterases 86

Contents VII

7.6.1Glucuronyland Sulpho-Transferases 90

7.6.2Methyl Transferases 92

7.6.3Glutathione-S-Transferases 93

8Toxicity 99

8.1Toxicity Findings 99

8.1.1Pharmacophore-induced Toxicity 99

8.1.2Structure-related Toxicity 101

8.1.3Metabolism-induced Toxicity 102

8.2Epoxides 103

8.3Quinone Imines 104

8.4Nitrenium Ions 109

8.5Imminium Ions 110

8.6Hydroxylamines 111

8.7Thiophene Rings 112

8.8Thioureas 114

8.9Chloroquinolines 114

8.12Toxicogenomics 116

8.13 Enzyme Induction (CYP3A4) and Drug Design 117

References 121

9Inter-Species Scaling 123

9.2Allometric Scaling 124

9.2.1 Volume of Distribution 124

9.2.2Clearance 126

9.6Elimination Half-life 131 References 132

10.3Physicochemistry 135

10.3.1Solubility 136

10.3.2Lipophilicity 136

VIII Contents

10.6Metabolism 137

10.8Outlook 139 References 140

Index 143

Pharmacokinetics and Metabolism in Drug Design IX

Edited by D. A. Smith, H. van de Waterbeemd, D. K. Walker, R. Mannhold, H. Kubinyi, H. Timmerman Copyright © 2001 Wiley-VCH Verlag GmbH ISBNs: 3-527-30197-6 (Hardcover); 3-527-60021-3 (Electronic)

Preface

The present volume of the series Methods and Principles in Medicinal Chemistry focuses on the impact of pharmacokinetics and metabolism in Drug Design. Pharmacokinetics is the study of the kinetics of absorption, distribution, metabolism, and excretion of drugs and their pharmacologic, therapeutic, or toxic response in animals and man.

In the last 10 years drug discovery has changed rapidly. Combinatorial chemistry and high-throughput screening have been introduced widely and now form the core of the Discovery organizations of major pharmaceutical and many small biotech companies. However, the hurdles between a hit, a lead, a clinical candidate, and a successful drug can be enormous.

The main reasons for attrition during development include pharmacokinetics and toxicity. Common to both is drug metabolism. The science of drug metabolism has developed over the last 30 years from a purely supporting activity trying to make the best out of a development compound, to a mature partner in drug discovery. Drug metabolism departments are now working closely together with project teams to discover well-balanced clinical candidates with a good chance of survival during development.

The present volume draws on the long career in drug metabolism and experience in the pharmaceutical industry of Dennis Smith. Together with his colleagues Han van de Waterbeemd and Don Walker, all key issues in pharmacokinetics and drug metabolism, including molecular toxicology have been covered, making the medicinal chemist feel at home with this highly important topic.

After a short introduction on physicochemistry, a number of chapters deal with pharmacokinetics, absorption, distribution, and clearance. Metabolism and toxicity are discussed in depth. In a further chapter species differences are compared and in- ter-species scaling is introduced. The final chapter deals with high(er) throughput ADME studies, the most recent trend to keep pace with similar paradigms in other areas of the industry, such as chemistry.

This book is a reflection of today's knowledge in drug metabolism and pharmacokinetics. However, there is more to come, when in the future the role and function of various transporters is better understood and predictive methods have matured further.

As series editors we would like to thank the authors for their efforts in bringing this book to completion. No doubt the rich experience of the authors expressed in

XPreface

this volume will be of great value to many medicinal chemists, experienced or junior, and this volume will be a treasure in many laboratories engaged in the synthesis of drugs.

Last, but not least we wish to express our gratitude to Gudrun Walter and Frank Weinreich from Wiley-VCH publishers for the fruitful collaboration.