Pharmacokinetics and Metabolism in Drug Design by Dennis A. Smith, Han Van De Waterbeemd and Don K

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 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) Methods and Principles in Medicinal Chemistry Edited by R. Mannhold H. Kubinyi H. Timmerman Editorial Board G. Folkers, H.-D. Höltje, J.Vacca, H. van de Waterbeemd, T.Wieland 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 Weinheim – New-York – Chichester – Brisbane – Singapore – Toronto 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) Series Editors: This book was carefully produced. Never- Prof. Dr. Raimund Mannhold theless, authors, editors and publisher Biomedical Research Center do not warrant the information contained Molecular Drug Research Group therein to be free of errors. Readers are ad- Heinrich-Heine-Universität vised to keep in mind that statements, data, Universitätsstraße 1 illustrations, procedural details or other D-40225 Düsseldorf items may inadvertently be inaccurate. Germany Library of Congress Card No.: Prof. Dr. Hugo Kubinyi applied for BASF AG Ludwigshafen c/o Donnersbergstraße 9 British Library Cataloguing-in-Publication Data D-67256 Weisenheim am Sand A catalogue record for this book is Germany available from the British Library. Prof. Dr. Hendrik Timmerman Die Deutsche Bibliothek – CIP Cataloguing- Faculty of Chemistry in-Publication Data Dept. of Pharmacochemistry A catalogue record for this publication is Free University of Amsterdam available from Die Deutsche Bibliothek De Boelelaan 1083 NL-1081 HV Amsterdam © Wiley-VCH Verlag GmbH, Weinheim; The Netherlands 2001 Dr. Dennis A. Smith All rights reserved (including those of Dr. Han van de Waterbeemd translation into other languages). Don K.Walker No part of this book may be reproduced Pfizer Global Research and Development in any form – by photoprinting, micro- Sandwich Laboratories film, or any other means – nor transmitted Department of Drug Metabolism or translated into a machine language Sandwich, Kent CT13 9NJ without written permission from the UK publishers. Printed in the Federal Republic of Germany Printed on acid-free paper Cover Design Gunther Schulz, Fußgönnheim Typesetting TypoDesign Hecker GmbH, Leimen Printing Strauss Offsetdruck, Mörlenbach Binding Osswald & Co., Neustadt (Weinstraße) ISBN 3-527-30197-6 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 1 Physicochemistry 1 1.1 Physicochemistry and Pharmacokinetics 2 1.2 Partition and Distribution Coefficient as Measures of Lipophilicity 2 1.3 Limitations in the Use of 1-Octanol 5 1.4 Further Understanding of log P 6 1.4.1 Unravelling the Principal Contributions to log P 6 1.4.2 Hydrogen Bonding 6 1.4.3 Molecular Size and Shape 8 1.5 Alternative Lipophilicity Scales 8 1.6 Computational Approaches to Lipophilicity 9 1.7 Membrane Systems to Study Drug Behaviour 10 References 12 2 Pharmacokinetics 15 2.1 Setting the Scene 16 2.2 Intravenous Administration: Volume of Distribution 17 2.3 Intravenous Administration: Clearance 18 2.4 Intravenous Administration: Clearance and Half-life 19 2.5 Intravenous Administration: Infusion 20 2.6 Oral Administration 22 2.7 Repeated Doses 23 2.8 Development of the Unbound (Free) Drug Model 24 2.9 Unbound Drug and Drug Action 25 2.10 Unbound Drug Model and Barriers to Equilibrium 27 2.11 Slow Offset Compounds 29 2.12 Factors Governing Unbound Drug Concentration 31 References 34 VI Contents 3 Absorption 35 3.1 The Absorption Process 35 3.2 Dissolution 36 3.3 Membrane Transfer 37 3.4 Barriers to Membrane Transfer 41 3.5 Models for Absorption Estimation 44 3.6 Estimation of Absorption Potential 44 3.7 Computational Approaches 45 References 46 4 Distribution 47 4.1 Membrane Transfer Access to the Target 47 4.2 Brain Penetration 48 4.3 Volume of Distribution and Duration 51 4.4 Distribution and Tmax 56 References 57 5 Clearance 59 5.1 The Clearance Processes 59 5.2 Role of Transport Proteins in Drug Clearance 60 5.3 Interplay Between Metabolic and Renal Clearance 62 5.4 Role of Lipophilicity in Drug Clearance 63 References 66 6 Renal Clearance 67 6.1 Kidney Anatomy and Function 67 6.2 Lipophilicity and Reabsorption by the Kidney 68 6.3 Effect of Charge on Renal Clearance 69 6.4 Plasma Protein Binding and Renal Clearance 69 6.5 Balancing Renal Clearance and Absorption 70 6.6 Renal Clearance and Drug Design 71 References 73 7 Metabolic (Hepatic) Clearance 75 7.1 Function of Metabolism (Biotransformation) 75 7.2 Cytochrome P450 76 7.2.1 Catalytic Selectivity of CYP2D6 78 7.2.2 Catalytic Selectivity of CYP2C9 80 7.2.3 Catalytic Selectivity of CYP3A4 81 7.3 Oxidative Metabolism and Drug Design 85 7.4 Non-Specific Esterases 86 7.4.1 Function of Esterases 86 7.4.2 Ester Drugs as Intravenous and Topical Agents 88 7.5 Pro-drugs to Aid Membrane Transfer 89 7.6 Enzymes Catalysing Drug Conjugation 90 Contents VII 7.6.1 Glucuronyl- and Sulpho-Transferases 90 7.6.2 Methyl Transferases 92 7.6.3 Glutathione-S-Transferases 93 7.7 Stability to Conjugation Processes 93 7.8 Pharmacodynamics and Conjugation 95 References 97 8 Toxicity 99 8.1 Toxicity Findings 99 8.1.1 Pharmacophore-induced Toxicity 99 8.1.2 Structure-related Toxicity 101 8.1.3 Metabolism-induced Toxicity 102 8.2 Epoxides 103 8.3 Quinone Imines 104 8.4 Nitrenium Ions 109 8.5 Imminium Ions 110 8.6 Hydroxylamines 111 8.7 Thiophene Rings 112 8.8 Thioureas 114 8.9 Chloroquinolines 114 8.10 Stratification of Toxicity 115 8.11 Toxicity Prediction - Computational Toxicology 115 8.12 Toxicogenomics 116 8.13 Enzyme Induction (CYP3A4) and Drug Design 117 References 121 9 Inter-Species Scaling 123 9.1 Objectives of Inter-Species Scaling 124 9.2 Allometric Scaling 124 9.2.1 Volume of Distribution 124 9.2.2 Clearance 126 9.3 Species Scaling: Adjusting for Maximum Life Span Potential 128 9.4 Species Scaling: Incorporating Differences in Metabolic Clearance 128 9.5 Inter-Species Scaling for Clearance by Hepatic Uptake 129 9.6 Elimination Half-life 131 References 132 10 High(er) Throughput ADME Studies 133 10.1 The HTS Trend 133 10.2 Drug Metabolism and Discovery Screening Sequences 134 10.3 Physicochemistry 135 10.3.1 Solubility 136 10.3.2 Lipophilicity 136 10.4 Absorption / Permeability 136 10.5 Pharmacokinetics 137 VIII Contents 10.6 Metabolism 137 10.7 Computational Approaches in PK and Metabolism 138 10.7.1 QSPR and QSMR 138 10.7.2 PK Predictions Using QSAR and Neural Networks 138 10.7.3 Physiologically-Based Pharmacokinetic (PBPK) Modelling 139 10.8 Outlook 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. Phar- macokinetics 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 dis- cover 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 inter-species scaling is introduced.

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