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Methods and Principles in Medicinal Chemistry - Mannhold R.

Methods and Principles in Medicinal Chemistry

Author: Mannhold R.
Other authors: Kubinyi H., Timmerman H.
Publishers: Wiley-VCH
Year of publication: 2001
Number of pages: 155
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Download: pharmacokinetiksmedicanalchemistri2001.pdf

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. Holtje, 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
® WILEY-VCH
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:
Prof. Dr. Raimund Mannhold
Biomedical Research Center Molecular Drug Research Group Heinrich-Heine-Universitat Universitatsstratee 1 D-40225 Dtisseldorf Germany
Prof. Dr. Hugo Kubinyi
BASF AG Ludwigshafen c/o Donnersbergstratee 9 D-67256 Weisenheim am Sand Germany
This book was carefully produced. Nevertheless, authors, editors and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.
Library of Congress Card No.:
applied for
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library.
Prof. Dr. Hendrik Timmerman
Faculty of Chemistry Dept. of Pharmacochemistry Free University of Amsterdam De Boelelaan 1083 NL-1081 HV Amsterdam The Netherlands
Die Deutsche Bibliothek - CIP Cataloguing-in-Publication Data
A catalogue record for this publication is available from Die Deutsche Bibliothek
© Wiley-VCH Verlag GmbH, Weinheim; 2001
Dr. Dennis A. Smith
Dr. Han van de Waterbeemd
Don K. Walker
Pfizer Global Research and Development Sandwich Laboratories Department of Drug Metabolism Sandwich, Kent CT13 9NJ UK
All rights reserved (including those of translation into other languages).
No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into a machine language without written permission from the publishers.
Printed in the Federal Republic of Germany
Printed on acid-free paper
Cover Design Gunther Schulz, Futegonnheim
Typesetting TypoDesign Hecker GmbH, Leimen
Printing Strauss Offsetdruck,
Morlenbach
Binding Osswald & Co.,
Neustadt (Weinstratee)
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
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