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The following message was posted to: PharmPK
Dear all,
Can anyone suggest a general inhibitor of peptide transporters
(uptake) in the gut? I have a compound with a dipeptide-like
structure that despite an almost negligible permeability in CACO-2
assays still shows good oral bioavailability in animals (mice, rats,
and dogs). Now, I would like to repeat the oral PK studies in these
animals in the presence of a transport inhibitor, just for proof of
concept. I'd appreciate any references.
Thanks in advance
Edgar
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Dear Edgar,
Food can be a good inhibitor of peptide uptake. We saw a big
negative effect with compounds that were tripeptides with c-terminal
ARG. There's probably some sort of tryptic peptide transport that is
saturated by the food.
Tom
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Edgar,
Try this website
http://bigfoot.med.unc.edu/watkinsLab/website/intesinfo.htm
all the best
Whocely
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The following message was posted to: PharmPK
Edgar
If your peptide is small and hydrophilic then it seems highly likely
to me that your peptide is not being absorbed by a transporter but
via the paracellular route, which is extremely weak in Caco-2.
Recently we have been trying to demonstrate that ampicillin is
absorbed via the Pept-1 transporter in rat intestine in vitro. Our
system (the improved everted gut sac) is much more physiological than
Caco-2. Try as we could, with a lot of different types of
experiments, including excess inhibitors, we were never able to
demonstrate transporter activity: everything pointed to paracellular.
Regards
John
John Woodley
Universite Paul Sabatier Toulouse III
Faculte des Sciences Pharmaceutiques
Laboratoire: Cinetique des Xenobiotiques
31062 Toulouse cedex 09, France
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