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Dear Group,
The most common way of measuring tissue
concentrations of NCE is from tissue homogenates,
which are infact produced when interstitial fluid or
extra-cellular compartment and the intra-cellular
compartments of tissues are mixed together. However
drugs often vary in their distribution between two
compartments for instance, beta-lactam antibiotics
give high levels in interstitial fluids akin to serum,
but very low to undetectable levels in tissue
intra-cellular fluid. On the other hand
fluoroquinolones are known to produce low interstitial
fluid and serum concentrations, but very high levels
in intracellular fluid. Since the intracellular
compartment is usually of larger volume than
interstitial fluids, tissue homogenates give lower
levels than serum for beta-lactams and much higher
levels than serum for fluoroquinolones.
Is it appropriate to correlate the concentration of
NCE in serum with tissue homogenate rather correlating
with interstitial tissue fluid? If not, how to go
about the determination of NCE concentration in
extra-cellular or interstitial tissue fluid? I would
appreciate the simple practical approach in evaluation
of pharmacokinetics of NCE in interstitial fluid.
Thanks in advance
Regards,
S Syed Mustafa,
Research Associate,
Drug Metabolism & Pharmacokinetics,
Discovery Research,
Dr Reddy's Lab Ltd,
Bollaram road, Miyapur,
Hyderabad- 500 049 INDIA
mustafas.-a-.drreddys.com
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Dear Syed Mustafa,
I am afraid there is no really easy way to assess the interstitial
concentration from plasma ot tissue concentrations. Although, at least
for small
molecules, the concentration in interstitial fluid will in most cases
be the
same than in the blood plasma of the respective organ, this does not
help much
because plasma concentrations in a periveral organ will deviate from
that in
venous plasma unless you are in a real steady state. Therefore
interstitial
concentrations in organs are determined by blood flow rates, tissue
permeation
rates and tissue to plasma partition coefficients.
In many cases the latter two parameters can be estimates quite well
from a few
in-vitro accessable substance specific parameters. This is particularly
the case
if the compound does not underly a dominant specific binding or active
transport
processes. Using such estimated data as input parameters it is possible
to
calculate the time course of concentration in different compartments
(e.g.
interstitial and cellular volume) of periveral organs with an
appropriate
physiology based pharmacokinetic model.
If total experimental tissue concentrations are are available those can
of
course be used to optimize a simulation in order to achieve a good
correlation
to the experimental knowledge if not given at all. The results of such a
PBPK-simulation will then give you a good overview about the behaviour
of you
compound in different organs and their subcompartments.
For some more information see http://www.pk-sim.com
Best Regards
Walter Schmitt
Bayer Technology Services GmbH
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Dear Syed Mustafa,
I am afraid there is no really easy way to assess the interstitial
concentration from plasma ot tissue concentrations. Although, at least
for small
molecules, the concentration in interstitial fluid will in most cases
be the
same than in the blood plasma of the respective organ, this does not
help much
because plasma concentrations in a periveral organ will deviate from
that in
venous plasma unless you are in a real steady state. Therefore
interstitial
concentrations in organs are determined by blood flow rates, tissue
permeation
rates and tissue to plasma partition coefficients.
In many cases the latter two parameters can be estimates quite well
from a few
in-vitro accessable substance specific parameters. This is particularly
the case
if the compound does not underly a dominant specific binding or active
transport
processes. Using such estimated data as input parameters it is possible
to
calculate the time course of concentration in different compartments
(e.g.
interstitial and cellular volume) of periveral organs with an
appropriate
physiology based pharmacokinetic model.
If total experimental tissue concentrations are are available those can
of
course be used to optimize a simulation in order to achieve a good
correlation
to the experimental knowledge if not given at all. The results of such a
PBPK-simulation will then give you a good overview about the behaviour
of you
compound in different organs and their subcompartments.
For some more information see http://www.pk-sim.com
Best Regards
Walter Schmitt
Bayer Technology Services GmbH
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Poulin & Thiel (J Pharm Sci v91 p129) distinguish those drugs that
readily
cross membranes from those that dont (by the way they helpfully present
data
for various extracellular tissue volumes). For those that dont readily
cross membranes, then the plasma concentration may be equal to the
tissue
extracellular fluid concentration, and it is the intra-cellular vs
extra-cellular concentrations that matter. I'm working on a substance
which
behaves in this way, and so my model lumps all extracellular fluids
together
with plasma, and considers the transfer between this pool and tissue
cells
in a more detailed way. A more conventional approach would be to
invoke one
or more "deep" tissue subcompartments to account for the kinetics seen,
but
I'm hoping my alternative will end up with a model with fewer
parameters,
especially fewer "fudge factors".
For substances that more readily cross membranes, a standard blood vs
tissue
model seems reasonable, on the assumption that the rate of crossing
memranes
is fast relative to the rate of supply of new substance to the tissue
via
the circulation,
Kim
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)