Radiotracers in Drug Development

320 Pages·2006·4.68 MB·English

by  Graham Lappin

Radiotracers
in
Drug
Development
This page intentionally left blank
Radiotracers
in
Drug
Development
Graham Lappin
Simon Temple
Boca Raton London New York
CRC is an imprint of the Taylor & Francis Group,
an informa business
3347_Discl.fm Page 1 Thursday, February 23, 2006 4:17 PM
Published in 2006 by
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2006 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group
No claim to original U.S. Government works
Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1
International Standard Book Number-10: 0-8493-3347-4 (Hardcover)
International Standard Book Number-13: 978-0-8493-3347-7 (Hardcover)
This book contains information obtained from authentic and highly regarded sources. Reprinted material is
quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts
have been made to publish reliable data and information, but the author and the publisher cannot assume
responsibility for the validity of all materials or for the consequences of their use.
No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,
mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and
recording, or in any information storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com
(http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive,
Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration
for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate
system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only
for identification and explanation without intent to infringe.
Library of Congress Cataloging-in-Publication Data
Catalog record is available from the Library of Congress
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
Taylor & Francis Group and the CRC Press Web site at
is the Academic Division of Informa plc. http://www.crcpress.com
3347_C000.fm Page v Tuesday, February 28, 2006 8:49 AM
The authors dedicate this book to their respective families,
Ann, Adam, Paul, and James (G.L.); Wendy, Philip,
and Richard (S.T.).
We thank them for their patience, tolerance, and support,
which made it all possible.
This page intentionally left blank
3347_C000.fm Page vii Tuesday, February 28, 2006 8:49 AM
Preface
Synthetic pharmaceuticals are xenobiotics; they are compounds foreign to human
metabolism and make no contribution to nutrition. Drugs, however, are not the only
xenobiotics to which we are all exposed. Take the diet, for example. Countless xeno-
biotics have evolved in plants, animals and bacteria as chemical defense mechanisms.
Other organisms that feed on them, such as humans, have coevolved biochemical
systems that neutralize and remove these toxins. This chemical warfare extends well
back in evolutionary time. Our detoxification mechanisms can be very efficient, evi-
denced by the fact that we do not experience toxic effects every time we ingest
xenobiotics not previously encountered as we try some new foodstuff. Pharmaceuticals
are xenobiotics that have been designed by humans to have targeted physiological
effects in the never-ending battle against disease. To the body, however, pharmaceu-
ticals are only another set of xenobiotics to be detoxified through metabolism and
excretion. To the body, no distinction is made as to whether the xenobiotic is a drug,
a synthetic chemical, or a natural compound. Indeed, this very fact goes some way to
explode the modern myth of natural = good, unnatural = bad. There is irony in the
fact that the body’s detoxification systems will potentially eliminate drugs that might
be lifesaving just as efficiently as other xenobiotics that might do harm.
Largely driven by the pharmaceutical industry, we now have a wide, yet still
growing, understanding of the enzymology responsible for xenobiotic metabolism.
Reflecting the influence of the pharmaceuticals industry, these enzymes are often
referred to as drug metabolizing, although as discussed above, from an evolutionary
perspective the presence of these enzymes has little to do with modern-day phar-
maceuticals. An understanding of the way the body deals with foreign compounds
is pivotal to developing effective new drugs. A drug might be exceedingly active in
the test tube, but if the body breaks it down and excretes it so rapidly that the effect
is not manifest in the patient, then the drug is of little use.
Not surprisingly, therefore, interest in the metabolism of xenobiotics grew sig-
nificantly as the first pharmaceuticals were developed. To study the metabolic fate
of a xenobiotic, it has to be followed through the body as it passes through the
tissues and organs. Practically, this can be a very difficult process. The task demands
that small amounts of compound be quantified within a vast and complex array of
constitutive compounds. Moreover, as the xenobiotic is metabolized, its chemical
structure is changed by metabolism, and therefore, in effect, it can hide from detec-
tion. These problems have been largely solved by the use of radiotracers, the subject
of this book. By introducing a “tag” onto the xenobiotic, it effectively contains a
radioactive homing signal, enabling the metabolic fate of the compound to be
followed through the biological system. This approach has been used as a general
research tool for many years. Indeed, as we shall see in Chapter 1, the photosynthetic
pathway was elucidated back in the 1950s using just this technique.
If radiotracers are to be useful, they must be detected and quantified. There are
many methods of detecting or imaging the label, and the choice very much depends
upon the questions the experiments are designed to answer. Needless to say, there
are many pitfalls of which the researcher must be aware. This book attempts to
3347_C000.fm Page viii Tuesday, February 28, 2006 8:49 AM
provide a general background to the use of radiotracers in the development of new
pharmaceuticals and to place signposts over the pitfalls, in the hope that the
researcher will not fall in. In recent times, new technologies have arisen for the
detection and imaging of radiotracers, which have quietly revolutionized this science.
Some of these technologies are not yet widely known, and so they are covered here
in an attempt to spread the word.
The publishing of this book coincides with great angst in the pharmaceuticals
industry. It is easy to forget, but modern drug therapy has developed over a remark-
ably short period. In the span of a single lifetime we have moved from the handful
of drugs available at the end of the Second World War to the multi-billion dollar
pharmaceutical industry that we see today. Many observers believe, however, that
the pharmaceuticals industry today is in crisis. The number of new drugs approved
each year is on the decline, while research and development costs are on the increase.
If we have not already seen the last of the blockbuster drugs, many believe that their
demise is not far away. There has been much debate on how to innovate the drug
development process. No single technology will transform the pharmaceuticals
industry; instead, each will play its own small yet important role. One of the many
innovations has been to reevaluate the role that radiotracers play in drug develop-
ment. Studies utilizing the unique properties of radiotracers are being conducted
earlier in the development cycle, and greater use is being made of data derived from
humans, as opposed to animal or in vitro models. Sizeable changes are afoot,
although the conservatism of the pharmaceuticals industry should not be underesti-
mated. There are few revolutions in this industry; it is more a matter of evolution
and slow evolution at that.
Pharmaceutical development is a highly interdisciplinary field. This book touches
upon only one aspect of drug development, but nevertheless, it crosses the boundaries
of biology, chemistry, and physics. Researchers therefore have to be highly flexible
and must be capable and willing to venture into fields where previously they had
little knowledge or experience. For many, this is the joy of science, but it can also
be frustrating, as the literature on the whole is written by experts for experts. This
book is therefore aimed at both those new to metabolism research and those who
are making the exciting journey to fresh pastures. It is not an in-depth review, but
more an overview; nevertheless, it is hoped that even the most experienced metab-
olism scientist will find this a useful source of reference. This book attempts to place
the use of radiotracer studies in context of the registration of drugs, and hence, it
has a strong bias toward an industrial approach. Notwithstanding this, it is hoped
that anyone researching into the metabolic fate of xenobiotics in general will find
parts of the text useful.
Graham Lappin
Cross-References
Throughout the text there are cross-references to other sections by the section
number: for example, 1.2.2, the first number (in this case 1) always indicating the
chapter.
3347_C000.fm Page ix Tuesday, February 28, 2006 8:49 AM
Authors
Graham Lappin
Dr. Graham Lappin, a veteran of 25 years in the business, started by researching
into the metabolism of terpenoids in plants. He earned his bachelor's degree and
Ph.D. from the University of Westminster, London, UK, followed by post-doctorial
research at the University of Glasgow in Scotland. Graham then spent several years
specializing in mammalian metabolism, and today he is dedicated to the study of
drug metabolism in humans. Widely published in his field, Graham is a fellow of
the UK's Institute of Biology and Royal Society of Chemistry, and is currently the
head of research and development at Xceleron Ltd., a spin-out from the University
of York, specializing in accelerator mass spectrometry. He would welcome any
comments or question relating to this book via e-mail ([email protected]).
Simon Temple
After qualifying as a teacher in 1972, Simon Temple worked for two years in
education. He left to pursue a career in sales with various companies in the scientific
market place working on a range of different product types. In 1984 he joined Packard
Instruments and in 1988 became responsible for the sales and marketing of the liquid
scintillation consumable products. From this time he became closely involved with
liquid scintillation products eventually becoming in 1995 the specialist responsible for
both internal staff and customer training.
From 1995 until he left the company (by then PerkinElmer Life Sciences) he was
closely involved in all aspects of liquid scintillation and gamma counting including
flow scintillation analysis and microplate scintillation counting. A short while after
leaving Perkin Elmer he formed DPM Solutions Ltd, a company dedicated to training
in the theory and practice of liquid scintillation counting and gamma counting.
Simon runs training courses on liquid scintillation and gamma counting and acts
as a consultant to various companies in the UK. He has recently become the managing
director of raytest UK Ltd, concerned with the sales and service of radiochromatog-
raphy, PET analysis and radiation protection instrumentation in the UK.