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Hello,
As a technician who has done preclinical animal biodistribution
studies for thirty years in nuclear medicine imaging research, more
recently targeting receptors, I agree that such testing is still
needed, but that autoradiographic techniques can also be used, in
which normal mouse or rat organ slices can be treated with labeled
ligands, rinsed, and then uptake in receptors/target tissue
components can be studied by frozen section autoradiography.
One problem in using animals for research is the diminishing pool of
those skilled or willing to learn to be skilled in injecting rodents
intravenously, especially using isotopes. Further problems are the
ever-increasing strictness of animal protocol review committees, who
often insist on analgesia being used in such experimental subjects;
this adds a variable which can affect the distribution of compounds.
On the bright side, the NIH and other funding agencies are
mounting new initiatives to encourage such research and build up the
infrastructure: creating core facilities for small animal imaging,
rodent histopathology, development of new PET imaging agents, cross
registration methodologies for CT/MRI/PET, etc.
Many pharmaceuticals already on the market have been tested for
biodistribution using labeled versions. Also, the required toxicity
tests will give a good indication of which organs take up the
majority of a compound. PubMed or Google searches can turn up results
from the nuclear medicine literature if the drugs have been tested
using labeled versions.
In this thread, I was concerned by one of the questioner's
seeming assumptions that anything injected or administered by a
particular route would travel through the bloodstream with the same
parameters, e.g. to the same targets, or in the same time course.
This isn't the case, obviously, or we wouldn't have been able to
develop different agents to scan particular organs or diseased
tissues. Or in everyday terms, different foods wouldn't give us
different sorts of satisfactions or distress.
I do agree with the curiosity and the need to study such things
further. The emphasis is rapidly going towards determining the
genetic causes and therapies for diseases or metabolic problems; to
this end, many new non-radioactive methods are being developed,
involving automated analysis of fluorescent probes, etc. I agree that
it's extremely difficult/expensive for one laboratory to excel in all
of these techniques; core facilities within research centers are the
reasonable solution; data-sharing and collaboration are encouraged by
the funding agencies, to limit unnecessary overlap.
Alice Carmel, Boston
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Dear Ms. Carmel,
In your letter of April 8, you are referring to "targeting receptors" and
the use of autoradiographic techniques in preclinical animal
biodistribution studies of "uptake in receptor/target tissue."
We agree, this kind of information should be an important part of
pharmacokinetics and people need to be trained in related in vivo imaging
techniques that include high resolution Receptor Micro Autoradiography. It
is encouraging to learn that "the NIH and other funding agencies are
mounting new initiatives to encourage such research and build up the
infrastructure"
The subject of receptor-ligand pharmacokinetics was discussed in January
of 2001 and the record of it can be found in: Pharm PK Discussion - in
vivo drug distribution studies: http://www.boomer.org/pkin
The outcome of this discussion was the amazing revelation that ADME
studies at pharmaceutical companies do not provide information on in vivo
receptor-ligand pharmacokinetics and that current pharmacokinetic studies
inform predominantly about drug distribution to secondary binding
sites. These are not identical with low capacity high specificity receptor
sites of action.
Pharmacokinetics of receptor binding, for instance as determined by in
vivo Receptor Micro Autoradiography, may be quite different compared to
tissue and plasma pharmacokinetics determined by radioassay/HPLC. We have
shown this to be the case for vitamin D and analog, and it can be expected
to be similar for other compounds as well.
In order to facilitate the study of receptor binding at cellular and
tissue levels, I am now completing a monograph that will become available
later this year and should be of help to investigators and
technicians. The title is:
RECEPTOR MICROSCOPIC AUTORADIOGRAPHY- METHOD MANUAL
for Tissue-Cell Localization and Characterization of Drugs and Hormones
(Delivery and Deposition, Receptor Binding, Targeting and Prediction)
Walter E. Stumpf, Chapel Hill
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)