Drug Localization in Tissues and Cells. Receptor Microscopic
Author: Walter E Stumpf.
ISBN 0-9740515-0-0. Library of Congress Control Number 2003105179.
IDDC-Press, Chapel Hill, NC. July 2003. 170 pages with color plates. $ 164.--.
The book is available through the University of North Carolina
Bookstore in Chapel Hill (UNC Student Stores, Chapel Hill , NC 27599 ).
Where do drugs act in the body? Which are the targets for desired therapeutic effects,
for other depositions that may lead to side effects or engender toxicity? What are the
routes of drug distribution, metabolism, and excretion? How much of a certain drug is
bound to receptors, what is the duration of binding, and how does this relate to action?
In order to answer such important questions, detailed information about in vivo sites of
drug deposition is essential. Techniques with high resolution and high sensitivity are
required. Since organs and tissues are composed of different cell types with different
functions, cells and specific cell populations need to be properly identified and
diagnosed. And since low numbers of molecules can act at specific cells and receptors,
their detection must be made possible. For that, microscopic resolution is necessary.
While current non-invasive scanning methods, as well as whole body autoradiography and
conventional radioassay-HPLC with excised organs or pieces of them, are valuable to gain
insight into drug distribution rates in blood, metabolic organs, excretory fluids, and
other high capacity/low specificity sites, they lack both resolution and sensitivity.
These expedient methods are unfortunately unable to identify high specificity/low
capacity receptor sites of drug action. Likewise, results from in vitro techniques,
although helpful, cannot be used as a substitute for receptor binding of drugs under in
vivo conditions. Receptor Micro Autoradiography, as detailed in this book, was developed
for the microscopic tissue localization of drugs, autacoids and xenobiotics,
non-covalently bound molecules in general. The method is based on the use of radiolabeled
compounds with high specific activity in conjunction with nuclear emulsion, and with
tissue preparation that preserves in situ conditions. Cellular-subcellular detail can be
viewed, associated radioactivity characterized and quantified, and time- and dose-related
data of different compounds compared. This manual contains instructions on experimental
design, execution, and evaluation of autoradiograms. Precise localization is documented
to provide important clues for function and to serve as a guide for further
histochemical, biochemical, functional, and clinical follow-ups for the development of
new therapeutic applications.
Receptor Micro Autoradiography, with its high diagnostic and predictive values, is an
indispensable tool for drug research and development.
Table of Contents
- Examples of Autoradiograms 95
Plate 1. 3H-Mesobilirubinogen, Liver 98
Plate 2. 3H-Estradiol, Uterus, Brain 100
Plate 3. Stria Terminalis, Estrogen Target Neuron Circuit, Allocortex-Brainstem-Core (ABC) Circuitry 102
Plate 4. 3H-Progesterone, Uterine Cervix; 3H-Org 2058, Brain 104
Plate 5.3H-1,25(OH)2Vitamin D3, Brain, Spinal Cord 106
Plate 6. 3H-1,25(OH)2Vitamin D3, Pituitary 108
Plate 7.3H-1,25(OH)2Vitamin D3, Parathyroid, Thyroid 110
Plate 8.3H-1,25(OH)2Vitamin D3, Heart 112
Plate 9.3H-1,25(OH)2Vitamin D3, Spleen 114
Plate 10.3H-1,25(OH)2Vitamin D3, Adrenal 116
Plate 11.3H- 1,25(OH)2Vitamin D3, Stomach 118
Plate 12. 3H-1,25(OH)2Vitamin D3, Pylorus, Duodenum 120
Plate 13. 3H-1,25(OH)2Vitamin D3, Small Intestine 122
Plate 14. 3H-1,25(OH)2Vitamin D3, Pancreas 124
Plate 15.3H-1,25(OH)2Vitamin D3, Testis, Kidney 126
Plate 16. 3H-Oxa-Calcitriol (OCT), Bone 128
Plate 17. 3H-Oxa-Calcitriol (OCT), Cancer Xenograft, Skin 130
Plate 18. Vitamin D Receptor "Drug Homunculus" 132
Plate 19. Vitamin D (Soltriol) Biological Role 134
Plate 20. 3H-Oxa-Calcitriol (OCT), Whole Body Autoradiograms 136
Plate 21. Microtome-Cryostats 138
- Lessons Learned 141
- Chronology of Development of Techniques, Applications, and Discoveries 145
- Highlights 145
- Timeline of Development of Method, Related Discoveries, and New Concepts 147
- References for Autoradiography of Diffusible Compounds 155
- Selected Publications by the Author 155
- Additional References 166
- About the Author 169