Albert P. Li - Transporters and Drug-Metabolizing Enzymes in Drug Toxicity

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Edited by Albert P. Li

In Vitro ADMET Laboratories, Inc. Columbia, MD USA

This edition first published 2021

© 2021 by John Wiley & Sons, Inc.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Albert P. Li to be identified as the author of the editorial material in this work has been asserted in accordance with law.

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Limit of Liability/Disclaimer of Warranty In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging‐in‐Publication Data applied forISBN: 9781119170846

Cover design by Wiley

Cover image: Courtesy of Albert P. Li

A major goal of this book is to provide information to aid the advancement of experimental approaches to ensure drug safety in drug development. It should be of interest to students and researchers in drug metabolism, transport, and toxicology; practitioners in drug development; and governmental regulatory scientists.

The most challenging aspect of drug development is the selection of drug candidates with appropriate safety and efficacy to ensure regulatory approval and market acceptance. The paradigm of demonstration of safety and efficacy in preclinical animal models followed by human clinical trials needs to be refined. The inadequacy of animal models to predict human safety and efficacy is clearly illustrated by the estimated >90% clinical trial failure rate for candidates selected based on results of preclinical trials. Let us ponder this for a minute, despite the extensive time and resources spent in preclinical evaluation, 9 out of 10 candidates selected for clinical trial fail due to a host of factors, with the major ones being unexpected toxicity and/or lack of efficacy. Furthermore, numerous marketed drugs have been withdrawn or have their use limited due to severe, often idiosyncratic, adverse drug toxicity.

This book is intended to present information to overcome this challenge. Failure of preclinical studies to predict human safety and efficacy can be attributed to species differences in drug properties. The inability of clinical trials to eliminate drugs with idiosyncratic drug toxicity is likely due to the inadequate number of subjects employed in regulatory clinical trials to identify drugs causing severe idiosyncratic drug toxicity with an incidence of <1/5000. It is, therefore, of utmost importance to fully understand the key determinants of drug toxicity and apply the knowledge to identify drug candidates with human toxicity as well as to identify the at‐risk human populations.