Back to the Top
Hi all,
Can we comment on if a compound is subject to CNS efflux activity
just by looking at in vivo plasma and brain concentration-time profile
(with no supplemental in vitro pgp data)? I am not sure if it was just
a fluke that I faintly remember to have read something like this few
months back. And unfortunately, I am not able to find that reference.
Could anyone in group comment about its possibility or otherwise?
References if any would be most welcome.
Thanks
Back to the Top
I believe you cannot. Besides being a P-gp substrate, a small molecule
with high plasma exposure may have low total brain exposure for a
variety of reasons such as:
1. Pchem properties (e.g., logP, charge)
2. Substrate to other efflux transporters
3. High and/or tight plasma protein binding
4. Poor passive membrane permeability
Hope this helps.
Back to the Top
The following message was posted to: PharmPK
Perhaps if you provide additional details more comments could be made
relating more specifically to your observation
Back to the Top
If you want to confirm the pgp efflux of your compound in the brain,
you need to do in vivo study in Pgp deficient mouse (mdr1a -/-). You
can supplement your data with in vitro Pgp experiments, before going
in to the in vivo study.
The attached reference might be of some help to you.
Comments from the experts are invited.
Thanks
Dr. Tausif Ahmed
Principal Scientist,
DMPK, Sai Advantium Pharma Ltd., Pune
India
Back to the Top
Ed,
I was wondering if we could comment on CNS efflux/influx activity of
a compound by looking at the shape of plasma concentration-time and
brain concentration-time curves in rats.
I have few compounds where both plasma and brain concentration-time
curve are superimposable. Even for the compounds exhibiting very poor
or very strong CNS penetration, shapes of conc.-time curves are quite
identical for both plasma and brain tissues (putting concentration
differences aside). Although I dont have any in vitro permeability or
in vivo (knockout mice) confirmation, i was wondering if I can assume
that these compounds are passively transported across CNS. I agree
that this may not be true for the compounds which are not eliminated
from the brain over a period of sampling times.
In contrast, I have seen few compounds where the shapes of
concentration-time curve in plasma and brain are entirely different
(indicative of efflux/influx phenomenon?).
I know that the relationship between in vitro fu_plasma/fu_brain ratio
and in vivo CNS partion coefficient (kp/log BB for some people) of a
compound can tell us somewhat about this. For passively transported
compounds fuplasma/fubrain ratio is within 2-3 fold of fu_plasma/
fu_brain ratio and if this correlation is lost, it may indicate the
presence of active efflux/influx event.
Back to the Top
The best way to study this empirically is with the Culex system- other
approaches are available.
Plasma>CSF>parenchyma>Parenchyma>CSF>Plasma. There is then both the
CSF compartment and the parenchymal compartment. Efflux noticeable in
plasma vould be either from the CSF or from parenchyma. CSF>plasma
Back to the Top
The following message was posted to: PharmPK
Dear Satya,
I do not think you can determine whether a compound is actively
effluxed / influxed based solely on concentration / time curves in
brain and plasma. Time to equilibrium is influenced by free fraction
in brain, so that compounds transported passively across the BBB may
still take time to reach equilibrium. The following reference may help
clarify these considerations:
JPET (2005), 313(3), 1254-1262 - Liu et al - Evaluation of the time to
reach brain equilibrium.
Likewise I would think that for some compounds efflux / influx may be
significant and influence partition between plasma and brain, but this
may be established quite fast and be maintained in time so that B/P
may remain constant in time.
Patrice Larger
|
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "CNS efflux" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)