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The following message was posted to: PharmPK
Dear all, we have started the evaluation of Blood Brain Barrier models
for a drug optimization program and, unsurprisingly, we have not found
unequivocal indications concerning easy and practical BBB models. At
the present we have found elucidations about a lot of models in vitro
(brain microvessel endothelial cells, immortalized brain endothelial
cell lines, etc.), but all cell systems contain apparent major
limitations like non-optimal expression of carriers, species-specific
phenotypes, etc. In addition we presume that in vivo BBB models are
low-throughput for our drug optimization program. What do you think
about in silico BBB models? Are they only able mainly to predict
"passive" diffusion? Do you think there are in vitro models acceptable
for a screening program? Do you belive results in non brain-derived
cells (CaCo-2, MDCK, etc.) are useful to identify similar properties of
test compounds in BBB? Have you performed a drug-screening program
including BBB permeability evaluation before now?
Thank you in advance
Dr. Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA
PO Box 328
Via ai Söi
CH - 6807 Taverne - Switzerland
Tel. +410919354527
Fax +410919354512
e-mail: stefano.porzio.at.zambongroup.com
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The following message was posted to: PharmPK
Hello Stefano:
If an in vitro model is truly predictive of what will happen in vivo,
then
that would certainly favor this approach for initial screening - but
sooner
or later you have to try it in an animal. For the BBB, some of the old
screens like octanol/water partition may not be predictive at all, while
screens that indicate that the compound is a substrate for
p-glycoprotein
may be more helpful in eliminating some candidates. You have to look at
multiple screens and make a value judgement. It's very hard to beat in
vivo screening as a definitive answer. We do this routinely using an
automated blood sampler which also provides an animal activity monitor
(rotation + rearing) and allows us to do automated in vivo
microdialysis in
the same animal. The simultaneous blood sampling provides data profile
PK
for the drug in the plasma (or serum, or whole blood). The behavioral
monitor can be very instructive if the compound is potentially CNS
active
and you would compare at least one 24 hour period before dosing with any
postdose activity collected. The brain microdialysis probe provides a
sample that can be analyzed for either the drug, or specific
neurotransmitters. If the therapeutic intent of the drug is to target a
specific CNS system, then the screening is much more useful if you just
look for the same neurotransmitters in each sample instead of trying to
develop or modify an analytical method for each compound. For example,
if
the goal of your research program was to develop a new MAO inhibitor,
screening for changes in the ratio of dopamine:DOPAC pre vs postdose
could
be very informative. Yes, in vivo screens involve more work in setting
up
the experiment, but if each animal yields useful information about both
PK
and PD, then you've ultimately saved time by getting multiple answers
in a
short time period.
Candice B. Kissinger
Director of Research
BASi
Candice B. Kissinger
Culex Product Manager
BAS Bioanalytical Systems Inc.
2701 Kent Avenue
Purdue Industrial Research Park
West Lafayette IN 47906-1382
USA
Direct Telephone: 765-497-5810 FAX: 765-497-1102
"Helping Life Scientists Study the Science of Life"
Employment Opportunities: http://www.baspeople.com
Culex Automated Blood Sampler, and 'Chads for Vials':
http://www.culex.net
Primary Corporate Website: http://www.bioanalytical.com
Human Plasma Homocysteine Analysis: http://www.homocysteine-kit.com
Liquid Chromatography and Electrochemistry: http://www.epsilon-web.net
Current Separations Newsletter: http://www.currentseparations.com
BAS is a charter member of PICRA, the Pharmaceutical Industry Contract
Research Alliance http://www.picra.org
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The following message was posted to: PharmPK
Hello,
I am working on a drug delivery project to cross the bbb. I am seeking
a in vitro model for bbb but can't find a commercial one.
Unfortunately, I am not a biological student and not working in a
biological lab, so it's not easy for me to develop a primary brain
microvessel endothelial cell culture by myself.
I wonder if there is any commercial resource of the immorbilized bbb
cell lines.
Thanks for help.
Lirong
NUS
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