Radionuclide Imaging in Drug Research

332 Pages·1982·6.125 MB·English

by  D Ganderton (auth.), Clive George Wilson, John G. Hardy, M. Frier, S. S. Davis (eds.)

RADIONUCLIDE IMAGING IN DRUG RESEARCH
Radionuclide Itnaging
in Drug Research
Edited by Clive George Wilson and John G. Hardy
with M. Frier and S.S. Davis
qp
CROOM HE LI'v1
London & Canberra
© 1982 e.G. Wilson, J.G. Hardy, \1. Frier and S.S. Davis
Croom Helm Ltd, 2-10 St John's Road, London SWII
Softcover reprint of the hardcover I st edition 1982
British Library Cataloguin~ in Publication Data
Radionuclidc imaging in dru!! research.
\. Chemistry, Medical and pharmaceutical
2. Radioisotopes
I. Wilson, e.G.
615'.1901'5 RS421
ISBN 978-94-011-9730-4 ISBN 978-94-011-9728-1 (eBook)
001 10.1007/978-94-011-9728-1
CONTENTS
Contributors
Foreword
Preface
Chapters
1. Dosage Design - Past, Present and Future
D Ganderton 1
2. Radiopharmaceutical Targeting in
Nuclear Medicine
D H Keeling 13
3. Data Handling and Computation in
Radionuclide Studies
D C Barber 21
4. Choice of Radionuclides for
Scintigraphy
J D Kelly 39
5. Formulation of Radiopharmaceuticals
C R Lazarus 61
6. Quality Control of Radiopharmaceuticals
M Frier 75
7. Radiopharmaceutical Distribution
Studies in the Rat
Y Jean-Baptiste 85
8. Studies of Radiolabelled Preparations
in the Rabbit
C G Wilson, J G Hardy 89
9. The Utilisation of Short-Lived
Radionuclides in the Assessment of
Formulation and In Vivo Disposition
of Drugs
G A Digenis 103
10. Gastrointestinal Transit of Gamma
Emitting Radionuclide Labelled
Preparations
J T Fell, E Hunter, H Sharma 145
11. Use of Multiple Pinhole External
Scintigraphy to Monitor Tablet
Disintegration In Vivo
M C Theodorakis, M D Devous,
D R Simpson 153
12. Spreading Characteristics of
Proprietary Rectal Steroid Preparations
D J Hay 171
13. In Vivo Radioimmunodetection of Cancer
F H DeLand, E E Kim, D M Goldenberg 181
14. Therapeutic Aerosol Deposition
S P Newman, D Pavia, S W Clarke 203
15. The Evaluation of Parenterally
Administered Emulsion Formulations
S S Davis, P K Hansrani 217
16. In Vivo Distributions of 99mTC_
Labelled Liposomes
K Jeyasingh 243
17. Factors Influencing the Clearance
Rates ·of Colloidal Particles from the
Rabbit Knee Joint
I W Kellaway, R S ChaVlla 261
18. The Distribution of Radiolabelled
Drug in Animals Infected with
Cutaneous Leishmaniasis: Comparison
of Free and Liposome-Bound Sodium
Stibogluconate
R R C New, M L Chance, M Critchley 279
19. Poster Abstracts 289
M Frier
~9.1 (l_llC)-Acetate - An Agent for the Tomo
graphic Study of Myocardial Metabolism 290
~9.2 Bone Scanning in Breast Cancer:
Identification of the High-Risk
Patient to Increase Positive Yield 292
19.3 Analysis of Gastric Emptying: a
Standardised Technique 293
19.4 Intestinal Transit Time of 51Cr_
Labelled Pellets of Different
Densities 294
19.5 Deposition of Cobalt-57 in the Rat 296
19.6 Studies on the Systemic Bioavailability
of Buprenorphine by Various Routes
of Administration 301
19.7 The Clearance of Liposomes
Administered by the Intramuscular
Route 303
19.8 The Clearance of Polystyrene
Microspheres from an Intramuscular
Injection Site 307
19.9 The Clearance of Albumin Microspheres
from an Intramuscular Injection Site 310
19.10 Gastric Emptying of Oils in the Rat 315
19.11 Evaluation of an Oral Sustained
Release Preparation by Gamma
SCintigraphy 320
19.12 Spreading of Suppository Bases
Assessed with Histological and
Scintigraphic Techniques 322
19.13 Studies on Microencapsulation using
Radionuclides 324
Index 327
CONTRIBUTORS
D C Barber Royal Hallamshire Hospital,
Sheffield
M L Chance Liverpool School of Tropical
Medicine, Liverpool
R S Chawla University of London, London
S ,'J Clarke The Royal Free Hospital, London
M Critchley Liverpool Royal Infirmary,
Liverpool
S S Davis University of Nottingham,
Nottingham
F H DeLand University of Kentucky,
Lexington, U.S.A.
M D Devous University of Illinois, Urbana,
U.S.A.
G A Digenis University of Kentucky,
Lexington, U.S.A.
J T Fell University of Manchester,
Manchester
M Frier Queen's Medical Centre,
Nottingham
D Ganderton Imperial Chemical Industries
Limited, Macclesfield
D M Goldenberg University of Kentucky,
Lexington, U.S.A.
P K Hansrani University of Nottingham,
Nottingham
J G Hardy Queen's Medical Centre,
Nottingham
o J Hay Manchester Royal Infirmary,
Manchester
E Hunter University of Manchester,
Manchester
Y Jean-Baptiste Office des Rayonnements
Ionisants, Gif sur Yvette,
France
K Jeyasingh Charing Cross Hospital, London
o H Keeling Plymouth General Hospital,
Plymouth
I W Kellaway University of Wales Institute of
Science and Technology, Cardiff
J 0 Kelly Amersham International Limited,
Amersham
E E Kim University of Kentucky,
Lexington, U.S.A.
C R Lazarus Guy's Hospital, London
R R C New University of Liverpool,
Liverpool
S P Newman The Royal Free Hospital, London
o Pavia The Royal Free Hospital, London
H Sharma University of Manchester,
Manchester
o R Simpson University of Illinois, Urbana,
U.S.A.
M C Theodorakis University of Illinois, Urbana,
U.S.A.
C G Wilson University of Nottingham,
Nottingham
FOREWORD
The use of gamma-emitting radionuclides for
diagnostic imaging in nuclear medicine has been
established for many years. Sophisticated gamma ray
detecting camera systems and computer links enable
the clinical investigator to image different regions
of the body and to quantify organ function. Parallel
developments have also occurred in the field of
radiopharmaceuticals, and today a wide range of
products is available that will exhibit specific
uptake within target tissues following parenteral
administration. For example, radioiodide is taken
up by the thyroid and iodinated fatty acids can be
used to image the myocardium. Labelled antibodies
have been used with success to target certain
tumours.
The concept of targeting has also been
considered by pharmaceutical scientists who wish
to deliver drugs rather than radionuclides to
specific sites in the body. The systems that have
been employed are often physically similar to those
used as radiopharmaceuticals (for example colloids,
aerosols and liposomes). Furthermore, pioneering
work by Digenis and others in the United States
States and by Alpsten and co-workers (1976)in Sweden
had demonstrated the potential of gamma scintigraphy
for investigating the fate of tablets and capsules
in the gastrointestinal tract of man in a non
invasive way. In 1979, the Biopharmaceutics Research
Group at Nottingham together with academic
pharmacists from Manchester held a one-day syffiposium
at Nottingham University to discuss how radio
nuclides could be used in drug formulation studies
to provide better approaches for the delivery of
drugs to their sitesof action. This initial meeting
brought together scientists from a wide variety of
disciplines and showed clearly the various common
objectives in radiopharmacy and drug design.
A second symposium,of 3 days duration,was held
at Nottingham in the spring of 1981. The meeting
was attended by approximately 100 participants from
12 different countries and included pharmacists,
clinicians, biochemists, pharmacologists,
physiologists, medical physicists and chemists.
This book is a critically edited version of the
submitted papers and poster presentations.
The first part of the book is devoted to the
basic aspects of radiopharmaceuticals and diagnostic
imaging and is intended to provide the foundations
for subsequent chapters dealing with the specific
approaches to drugs and formulations. The use of
more rational approaches to drug dosage design are
gradually being accepted, with recognition of the
possible interaction between physicochemical and
physiological variables. The clinical uses of gamma
scintigraphy and the concepts of targeting are
considered and the important point that physiological
factors determine the imaging characteristics rather
than anatomical factors is made. The choice of
suitable tracers for scintigraphy is rather limited
from the standpoint of gamma ray spectra and half
lives of the radionuclides. In addition, the
chemistry and the formulation of suitable radio
pharmaceuticals presents challenges to the radio
pharmacist. It is possible in certain instances to
label the drug; more often it is an excipient of,or
additive to,the formulation which is tagged. Some
times physiological substrates such as albumin, red
blood cells or platelets are labelled. The choice
of the strategy employed depends on the nature of
the investigation, although in most instances it is
the formulation which is labelled. It is important
that the label is of the required stability and that
the carrier systems are of suitable purity. Finally,
the data handling and computational aspects of gamma
camera imaging must be mastered.
The next section of the book deals with the
present applications of scintigraphy in studies of
the behaviour of drugs in animal models and in man.
In considering animal studies the relevance of the
model to predicting behaviour in man must be
carefully considered.
Access to the cyclotron-produced short-lived
radiOisotopes of carbon, nitrogen and oxygen allows
drugs to be directly labelled, and the pharmaco
kinetics and deposition of the drugs to be studied
in a non-invasive fashion. However, for all but
the fortunate few, these facilities are too
expensive. Nevertheless, interesting and valuable
work has been carried out using the more readily