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Many drugs and other xenobiotics (e.g., preservatives, insecticides, and plastifiers) contain hydrolyzable moieties such as ester or amide groups. In biological media, such foreign compounds are, therefore, important substrates for hydrolytic reactions catalyzed by hydrolases or proceeding non-enzymatically. Despite their significance, until now, no book has been dedicated to hydrolysis and hydrolases in the metabolism of drugs and other xenobiotics. This work fills a gap in the literature and reviews metabolic reactions of hydrolysis and hydarion from the point of views of enzymes, substrates, and reactions.
Content: Chapter 1 Introduction: Metabolic Hydrolysis and Prodrug Design (pages 1–9): Chapter 2 Classification, Localization, and Some Physiological Roles of Hydrolytic Enzymes (pages 11–46): Chapter 3 Catalytic Mechanisms of Hydrolytic Enzymes (pages 47–79): Chapter 4 The Hydrolysis of Amides (pages 81–162): Chapter 5 The Hydrolysis of Lactams (pages 163–234): Chapter 6 The Hydrolysis of Peptides: Sections 6.1 – 6.3 (pages 235–311): Chapter 6 The Hydrolysis of Peptides: Sections 6.4 – 6.6 (pages 312–364): Chapter 7 The Hydrolysis of Carboxylic Acid Esters (pages 365–418): Chapter 8 The Hydrolysis of Carboxylic Acid Ester Prodrugs (pages 419–534): Chapter 9 The Cleavage of Esters of Inorganic Acids (pages 535–590): Chapter 10 The Hydration of Epoxides (pages 591–661): Chapter 11 Miscellaneous Reactions of Hydration and Dehydration (pages 663–748): Chapter 12 Conclusion: The Biochemistry of Water (pages 749–751):
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Hydrolysis in Drug and Prodrug Metabolism Chemistry, Biochemistry, and Enzymology
Hydrolysis in Drug and Prodrug Metabolism. Bernard Testa, Joachim M. Mayer © Verlag Helvetica Chimica Acta, Postfach, CH8042 Zürich, Switzerlaand, 2003
Hydrolysis in Drug and Prodrug Metabolism Chemistry, Biochemistry, and Enzymology Bernard Testa, Joachim M. Mayer
Verlag Helvetica Chimica Acta
Prof. Bernard Testa Institute of Medicinal Chemistry School of Pharmacy University of Lausanne CH-1015 Lausanne Switzerland
This book was carefully produced. Nevertheless, authors and publishers 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.
Published jointly by VHCA, Verlag Helvetica Chimica Acta AG, Zürich (Switzerland) WILEY-VCH GmbH & Co. KGaA, Weinheim (Federal Republic of Germany) Editorial Directors: Thomas Kolitzus, Dr. Patricia L. Bounds Production Manager: Norbert Wolz
Cover Design: Bettina Bank
Library of Congress Card No. applied for. A CIP catalogue record for this book is available from the British Library.
Bibliographic information published by Die Deutsche Bibliothek. Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available in the internet at http://dnb.ddb.de. ISBN 3-906390-25-X
© Verlag Helvetica Chimica Acta, Postfach, CH–8042 Zürich, Switzerland, 2003 Printed on acid-free paper. 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. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Printing: Konrad Triltsch, Print und Digitale Medien, D-97199 Ochsenfurt-Hohestadt Printed in Germany
Dedicated to the fond memory of Joachim M. Mayer (1949 – 2001) and Nabil El Tayar (1957 – 2001), former graduate students, colleagues