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Hi,
I am working with an investigator who has infused drug into the
lateral ventricle of the brain using an alzet minipump. They see
effects on brain function with this delivery mechanism. They want
now, though, to administer the compound IP to very young mice in order
to assess effects on development over time (~ 8 weeks). We believe
the compound makes it into the brain in fairly high levels based on
analysis of compound levels in lysate made by homogenizing the brain
after IP administration of compound over a range of time points. We
know the concentration achieved in the brain during minipump delivery
and would like to rationally determine a dose and schedule that could
reasonably achieve comparable steady state levels in the brain. All
of the calculations of steady state concentration I have found in PK
texts are based on calculations using plasma levels. For example,
Rowland and Tozer (Clinical Pharmacokinetics Concepts and
Applications, 3rd edition) pg 97 report that
Css,av = AUC(single dose)/tau
I have naively calculated AUC for the brain using the PK data I have
with the noncompartmental function of WinNonLin, although the model I
used was for plasma. I know the dosing interval we would like to use
(tau = 24 hours). Is it reasonable then to calculate the predicted
steady state concentration in the brain with this information? I know
there are also approaches for predicting Css min and Css max although
these require knowledge of F, which I don't yet know for this compound
(we're using IP delivery due to the size of the mice). If there are
better approaches for tissues, I would appreciate any advice. We're
in the process of actually measuring the levels achieved by a certain
dosing schedule, but I want to find out how reliable my rationale was
for future experiments.
Thank you,
Noelle
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The following message was posted to: PharmPK
You may find the following article helpful."Pharmacokinetics and
Pharmacodynamics of Alfentanil in P-Glycoprotein-Competent and
P-Glycoprotein-Deficient Mice: P-Glycoprotein Efflux Alters Alfentanil
Brain Disposition and Antinociception. J. Cory Kalvass, Emily R.
Olson, and Gary M. Pollack. DMD 35:455-459, 2007"
Eyob
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The following message was posted to: PharmPK
Have you perfused the animals prior to sampling??? Patricia Cserr has
done
a great deal of work with comprising the blood brain barrier using a
gradual
exposure of animals to hyperosmotic solutions- which opens up the
barrier.
She has assembled a great deal of data looking at distributions of
numerous
compounds across the blood brain and brain CSF barriers
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Do you want SS concs after IP dosing or mini pump infusion?
If IP dosing: One way you can do this is treat the brain compartment
as the sampling compartment, fit the data you have now using an
absorption model. Then once you have fit the data, then simulate for
diffrent doses and see what doses would produce what concentrations.
Not mechanistic but will serve the purpose.
If mini pump: Treat brain compartment as before and use infusion model.
Note that both of the approaches have many assumptions and are not
mechanistic at all.
Neil
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