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Dear all,
If we give a dose of 10mg/kg orally for a mouse species of 25g body
weight.
The dose given would be 250ug/mouse. Assuming roughtly 7% of the total
body
weight is the blood volume, then a 25g mouse will have 1.75ml of blood,
then
if we measure the plasma conc.(total drug) thearotically it should be
142.8ug/ml.
Is the above logic is right?
Is there any one in the group where you have seen the concentration of
the
drug administered in any of the species to be more (from the above
example
say >300ug/ml) if we are measuring total concentration in blood
(plasma). If
that is the case what may be the possible reasons?
Kind Regards,
Suresh.B.L
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Dear Suresh,
You're overlooking the erythrocyte binding, or the absence thereof. Some
drugs do not enter the ery's at all and in that case the concentration
can
be 2x the 142 ug/mL you mention, which nicely fits the 300 you find.
You can
confirm this by doing a ery binding experiment, i.e. spike fresh whole
blood
with the compound, allow for distribution and prepare plasma. Do
include a
control where you immediately separate plasma after spiking/mixing to
make
sure there are no stability issues. Also, to avoid redistribution
phenomena,
do all experiments at the same temperature. To make sure you simulate
what
happens in thoe mouse 37 degrees would be best but to prove your point
probably RT will work too.
Best regards, Jan
Jan de Jong, PhD
Preclinical Development
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
1000 US Rt. 202, Raritan, NJ 08869, USA
e-mail: jdejong1.aaa.prdus.jnj.com
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Dear Suresh,
I've some doubt regarding your experiment:
1- First of all you do not consider the route of administration, o.s.
administration generally doesn't allow to a generic drug a 100% of
absorption. try with i.v. route also
2- following the ADME you can't consider only one compartment (Blood)
without considering the metabolism of the drug and the excretion and
futhermore it is quite difficult that you have only one compartment
(Blood)
3- You speak of "Blood" but then you quantify your drung in "Plasma"
this is not coerent, you should try to quantify your compound in two
ways:
a- Total Blood (after osmotic shock of RBC) : if result is 1/2
of the one obtaine with plasma this means that your compound doesn't
enter into RBC
b- Quantify your compound in the RBC buffy coat after several
washing cycles with isotonic solution: if result is "0": same
consideration for point a
Let me know
Fabio Macchi
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Your calculation is right if you assume:
a) that your drug is not distributed outside of the central compartment
b) The whole dose is absorbed from the GI tract with very little
first-pass effect
Secondly if a) and b) are right, you have to factor in the fact that
the drug appear to be confined to the plasma compartment, it does not
bind to or penetrate into RBC. This would make sense in light of the
ca 300 ug/mL concentration you obtain, but I assume this concentration
was measured in plasma. To confirm this, you need to do some in-vitro
RBC partitioning study to find out the ratio of drug concentration
plasma/RBC.
Jean-Pierre Moreau
BDI
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Another possible artifact is not allowing time for distribution into the
total plasma or blood volume.
For example if you inject the drug into a vein and then immediately
sample
downstream before it has had time to make one complete circuit of the
vascular system you can get extremely high concentrations even if the
assumptions below do not hold.
R. Kavanagh
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)