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The following message was posted to: PharmPK
To all, what would be an adequate level of radioactivity (uCi/animal)
that can be given to mice knowing that the parent compound in mice has
an half-life of ca 10 hours. The object of the project is to do tissue
distribution of drug-derived radioactivity.
Thank you in advance,
Jean-Pierre Moreau
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The following message was posted to: PharmPK
Jean-Pierre:
In answer to your question:
what would be an adequate level of radioactivity (uCi/animal) that can
be given to mice knowing that the parent compound in mice has an
half-life of ca 10 hours.
the rule is that you need to have counts that are 10 times or more
above background in the sample to be measured at the time of counting
in order to get meaningful data. While the animal is alive, you need to
use the effective half-life to estimate what will be present in what
organ/tissue. Once you have euthanized the animal, you only need to
consider the physical half life of your radionuclide.
--
Professor Walter Wolf, Ph.D. President, Correlative Imaging Council,
Society of Nuclear Medicine
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
University of Southern California 1985 Zonal Ave., Los Angeles, CA
90089-9121
E-Mail: wwolfw.-at-.usc.edu
Telephone: 323-442-1405
Fax: 323-442-9804
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The following message was posted to: PharmPK
J-P,
What Isotope? If 14C I tend to give ~5 uCi/mouse, more with tritium
because of the lower counting efficiency. You can get away with less,
but I tend to use more on a per kg basis than one would use with rats
becasue they tend to clear things faster than rats. Also of course the
level you want to detect may be important, but this amount ususally
provided plenty of sensitivity.
Dale Sharp
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The following message was posted to: PharmPK
Jean-Pierre:
Selection of the dose for radioassay should be determined foremost by
the
objective of the study: deposition after a dosis efficax (low, medium,
or
high) or a toxic dose. Selection may further be influenced by the
specific
activity of the compound and the type of radiation of the tracer; also,
whether or not you are interested in finding out about target tissues
with
specific binding and retention or about sites of deposition in
low-specificity-high-capacity tissues, including those of metabolism and
excretion.
Detectability depends on the 'specific concentration' in tissue. This,
however, is not known and researched through the experiment.
A high dose that may give you "10 times or more above background",
pointed out
by Dr. Wolf as 'the rule', may or may not give the answer. It can be
assessed
only after data from the experiment are available.
In our studies that were aimed at the detection of and retention in
target
tissues, a rule of thumb has been 1-2 microCurie/gram bw. Uptake and
retention in blood, metabolic and excretory organs, may have quite
different
pharmacokinetic parameters compared to that of target tissues.
If the specific activity of your compound is low, the dose of drug
necessary
may be too high for the detection of low-capacity-high-specificity
binding
sites.
Not the dose of radioactivity, but the dose of drug should be the
determining
factor. Studies with too high a dose of drug - to compensate for low
specific
activity - may not be meaningful.
It is quite complex and there is no simple and uniform answer to your
question. Each compound requires special considerations. Pilot
experiments
may have to be conducted first with two or three different regimen.
Your question of dose is at the core of meaningful or not-so meaningful
pharmacokinetic studies. I am curious to see, what thoughts and
responses
emerge from those who conduct routine ADMET studies at pharmaceutical
companies.
Walter E. Stumpf
Chapel Hill, NC
(see also: http://www.unc.edu/~stumpfwe)
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)