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Hi,
I'm looking for publications or experiences
concerning following phenomenon:
Up to 2-4 hours after iv-administration one can
observe signif. different concentrations in blood (plasma)
dependent on different sites of sample withdrawl,
for eg. between blood from jugularis vein and tail vein of rats.
Does there exist any investigations concerning time-dependent
distribution
effects in blood in different parts of the organism (like portal vein
blood
vs peripheral blood)
Best regards
Manfred
Manfred Zimmer
Aventis Pharma Deutschland GmbH
DI&A, LO, DMPK
in-vivo PK / Special Analytics (QWBA)
65933 Frankfurt/Main
Industriepark Höchst, G 876, R225
Phone: +49 (69) 305-43661
e-mail: Manfred.Zimmer.-at-.aventis.com
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Dear Manfred,
Can you provide me with references for the statement below concerning
different drug concentrations depending on the site of sampling? I
would be most appreciative.
Best Regards,
Charles Engbers
ALZA Corp
Mountain View, CA USA
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The following message was posted to: PharmPKHi Manfred,
Here are some references that might be of help -there are lots of
others too, but I've been working with Richard Upton for a while and
these came easily to mind. So please excuse my biased list ;)
Basically, "blood" isn't just blood -it's not one homogeneous pool, for
example, pulmonary arterial blood goes in to the lungs and the blood
coming out the other side can have very different drug concentrations
after iv bolus administration as the lungs are often able to extract or
metabolise drugs. Indeed with rapid sampling after iv bolus you can
end up with Vc (from normal compartmental PK analysis) estimating the
apparent volume of distribution of the lungs. The longer you sample
for, the more concentrations in the different blood "pools"
equilibrate, a phenomenon that is determined by the distribution
kinetics (including organ blood flows in some cases!) for the organs
concerned.
Upton RN (2000) Relationships between steady state blood concentrations
and cardiac output during intravenous infusions.Biopharm Drug Dispos
21:69-76.
Upton RN and Doolette DJ (1999) Kinetic aspects of drug disposition in
the lungs.Clin Exp Pharmacol Physiol 26:381-391.
Upton RN and Ludbrook GL (1999) A model of the kinetics and dynamics of
induction of anaesthesia in sheep: variable estimation for thiopental
and comparison with propofol.Br J Anaesth 82:890-899.
Upton RN, Zheng DA, Grant C and Martinez AM (2000) Development and
validation of a recirculatory physiological model of the myocardial
concentrations of lignocaine after intravenous administration in
sheep.J Pharm Pharmacol 52:181-189.
Hope this helps,
David
David Foster, PhD
NHMRC Research Officer
Department of Clinical and Experimental Pharmacology
Faculty of Health Sciences
The University of Adelaide
Adelaide, South Australia 5005
Tel: +61 08 8303 5985
Fax: +61 08 8224 0685
Email: david.foster.-a-.adelaide.edu.au
http://www.adelaide.edu.au/Pharm/index.htm
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The following message was posted to: PharmPK
Hello Manfred:
It may not be the site -- it may instead be the sampling technique. If
your jugular vein withdrawal is being accomplished through use of an
intravenous catheter, while the tail vein sampling is done in a
restrained
rat after manipulation of the tail vein, or by nicking the vein, there
is a
difference in the comfort level of the animal as well. There can be a
very
dramatic difference in plasma catecholamine concentration in the same
rat
exposed to such differences in sampling methods. What influence does
this
catecholamine surge have on drug metabolism? It redirects blood flow by
interacting with receptors on the blood vessels -- making some of them
smaller and thus redirecting blood flow. Blood preferentially goes to
the
critical organs (fight or flight response) and the liver and kidney are
not
on that list. Therefore, there will be a difference in blood flow to
those
organs -- and this could result in a difference in the ability of the
body
to clear the drug.
We have demonstrated this in our lab using crossover studies in the same
rats, collection of blood, and analysis of plasma catecholamine
concentration as well as plasma drug/metabolite concentration.
Best Wishes,
Candice Kissinger
Senior V.P. Research
BASi
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The following message was posted to: PharmPK
I would be interested to know more about effects of drug levels on
sampling
site/technique. Particularly, regarding C. Kissinger's reply to M.
Zimmer:
"We have demonstrated this in our lab using crossover studies in the
same
rats, collection of blood, and analysis of plasma catecholamine
concentration as well as plasma drug/metabolite concentration."
I am curious to know what are the magnitudes of the effects of sampling
technique on drug concentration? How long does the stress have to
occur to
see an effect on relative drug concentrations? Or how long does the
stress
response last? I would be especially interested in any publications on
the
effects of sampling site/technique on drug levels in rodents.
Thanks in advance.
Tom Holt
Merck Research Laboratories
732-594-3412
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