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Dear all,
I would like to ask a question regarding single pass intestinal
perfusion.
Whether should we consider metabolism during passing through
intestinal segment? e.g. testoeterone is highly succeptible for
metabolism so while selecting this kind of molecule for screening
purpose should we consider metabolism as a loss of drug or
permeability across intestine ?
regards
rahul vats
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The following message was posted to: PharmPK
Rahul,
It depends on how the permeability coefficient (Papp) is calculated i.e.
whether using disappearance of the test compound from the perfusate
buffer or appearance of the test compound in the venous blood. When Papp
is calculated based on the appearance flux of the parent, compound lost
due to intestinal first-pass metabolism is considered as not being
absorbed. On the other hand, when Papp is calculated based on the
disappearance kinetics, drug metabolised in the intestine is not
considered as loss as it is an event occurring after the drug being
absorbed. However, calculating the Papp basing on compound disappearance
is prone to error, especially if the test compound is lipophilic (e.g.
testosterone), as compound loss could also be due to adsorption (to
perfusion apparatus, tissue adhesion, degradation etc. As a result, use
of appearance kinetics seems to be more appropriate as this takes into
consideration of efflux, metabolism, tissue retention etc.
Hope this helps.
Cheers,
Kasiram.
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The following message was posted to: PharmPK
Please note that the proper (FDA) definition of absorption is leaving
the
intestinal lumen and entering the enterocytes. Unfortunately, the term
absorption has been used several ways over the years. Sometimes it has
referred to the fraction of the dose reaching the portal vein (FDp) and
sometimes to the amount reaching the central circulation (F), but
these are
three different quantities that are distinct and need to be identified
properly.
In older papers such as those referring to Wagner-Nelson and Loo-
Riegelman
methods for deconvolution, the term absorption actual refers to systemic
availability, not absorption as it is now defined.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-a-.simulations-plus.com
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Dear Rahul
Yes you have to do the stability as well as metabolism of the drug in
intestinal microsomes and you can prepare very easily in your lab. It
is invitro method by use of the intestinal microsomes and same you can
monitor when your doing SPIP. As your monitoring Cout and Cin from
intestinal segment.
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sir i got different answers so can you elaborate?
According to your opinion i should go for microsomal stability study
before spip otherwise it will give false result in case where gut
metabolism is high.
rahul vats
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