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Dear all
while doing Caco-2 permeability studies of a NCE or marked product,
1.What parameters have to take into the consideration from PK point of
View
2. How to select the concentration for permeability studies (when we
don't know about the transport mechanism like passive or active )
3.What is the applicatioin, when we improving the permeability of
poorly soluble NCE by using serum albumin.( how exactly we can apply
to the invivo conditions).
4. Role of permeability studies in the regulatory filings.
Plz kindly reply
Thanks and regards
Ravindra
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dear ravindra
during caco-2 permeability assay
the conc is selected depending upon the human dose irrespective of
transport mechanism
the role of permeability study is to submit it in regulatory filings
as US FDA recommends the caco-2 assay for permeability testing
regards
Sachin Ramrao Patil,
NIPER, INDIA.
sachin_prits.aaa.yahoo.co.in
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The following message was posted to: PharmPK
Dear Ravindra,
1) Mostly, apparent permeability and existence of an active transport
(efflux or influx)
2) Papp is independent from concentration if transport is essentially
passive.
For first tests, you may consider that a drug given per os would
likely reach the intestine as a rather high concentration. 50uM is a
typical value, although you may be limited by solubility and try 20uM
or 10uM. On the other hand, the possibilities of decreasing the
concentration would be limited by the sensitivity of the analytical
method to assay what has reached the basolateral side (or you'd have
to increase the incubation duration to let the test compound
accumulate). However, detection of significant active transport, which
is theoretically saturatable, will be easier at low concentration;
ideally, the effect of concentration on permeability and efflux ratio
should be studied.
3) Use of albumin: a number of papers do exist, e.g. Saha P and Kou
JH, Eur J Pharm Biopharm 2002.
4) See the FDA guidances for Biopharmaceutical classification of drugs
and the draft guidance for drug-drug interactions (Sept 2006).
For items 1-3-4, a key point is to calibrate the model with a number
of reference drugs
Hope this helps a little bit.
Regards,
Frederic Massiere
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hi
i am working with caco-2 peremability studies of some high
permeability drugs. i want to know about how to determine the pathway
of passive drug transport i.e. whether it is paracellular or
transcellular. if i want to classify those drugs into passive
paracellular or passive transcellular route but
i dont know how to differentiate between their passive paracellular or
transcellular route.
thanks & regards
Sachin Patil
sachin_prits.at.yahoo.co.in
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Dear Sachin,
The following publications by Adson describe one method for
calculating the contribution of the paracellular route to overall
permeability. If transporters are not involved then the total
permeability - paracelluar = transcellular permeability. The
publications by Sugano describe a method to use artificial membrane
permeability and calculated paracellular permeability to reconstruct
human effective permeability.
Mike
Adson, A., T. J. Raub, et al. (1994). "Quantitative approaches to
delineate paracellular diffusion in cultured epithelial cell
monolayers." J Pharm Sci 83(11): 1529-36.
Adson, A., P. S. Burton, et al. (1995). "Passive diffusion of weak
organic electrolytes across Caco-2 cell monolayers: uncoupling the
contributions of hydrodynamic, transcellular, and paracellular
barriers." J Pharm Sci 84(10): 1197-204.
Sugano, K., N. Takata, et al. (2002). "Prediction of passive
intestinal absorption using bio-mimetic artificial membrane permeation
assay and the paracellular pathway model." Int J Pharm 241(2): 241-51.
Sugano, K., Y. Nabuchi, et al. (2003). "Prediction of human intestinal
permeability using artificial membrane permeability." Int J Pharm
257(1-2): 245-51.
* Michael B. Bolger, Ph.D.
* Chief Scientist
* Simulations Plus, Inc.
* 42505 10th Street West
* Lancaster, CA 93534
* U.S.A.
* http://www.simulations-plus.com (NASDAQ: SLP)
* bolger.-a-.simulations-plus.com
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