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From: YChugh.-at-.wockhardtin.com
Date: Mon, 9 Jun 2003 16:31:23 +0530
The following message was posted to: PharmPK
Our group is working on the PK
properties of a test drug which seems to be a substrate for pGP mediated efflux.
Verapamil and forskolin (both known inhibitors) increase the Cmax and AUC for
the test drug in rats. In addition to using pGP inhibitors, we made few ester
prodrugs of the compound. One of the esters (Methyl) gave an oral AUC about 6
times higher as compared to the native drug (5 vs 32) thereby taking the F% to
around 300 when calculated using i.v. AUC of the native compound. We than did
the the PK profiling of ester by i.v. route and compared the i.v. AUC's of the
ester prodrug with the native drug. I.V AUC's of the ester also increased
significantly. I am not so sure why this happens ?? - May be ester is inhibiting
the pGP mediated elimination ??
I would appreciate if some thoughts are shared on this.
Yati Chugh Ph.D
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From: "Vuong Trieu"
Date: Mon, 16 Jun 2003 09:21:54 -0700
Subject: RE: PharmPK PK properties of substrate for pGP mediated efflux
The following message was posted to: PharmPK
You might want to look up the clinical data on CsA and paclitaxel.
[Sorry about the double posting of a few days ago - db]
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The following message was posted to: PharmPK
Dear Dr.Chugh,
The phenomenon you are observing is really very strange. Ester form of
a drug acting as a P-gp inhibitor and on the contrary drug perse being
a P-gp substrate is really a phenomenon I never heard about.
Just I want to know clarify few things about your query.
Are you finding any levels for your methyl prodrug after administration
to the animal model. If so, uptill what time. If your prodrug is
immediately getting converted into parent drug, it cannot show any P-gp
inhibition.
Did you check the nature of your drug and its estar prodrug (with
refernnce to P-gp) on the Caco-2 cell system. This will really give you
a better insight into your problem.
As far as my knowledge regarding the ester prodrugs is concerned, they
are very labile and get immediately cleaved by esterases present in the
plasma. There can be differences in the rate of dissociation between
different prodrugs of the same drug tothe parent form, but as such
they are not stablein the plasma.In this context I want to know upto
whattime you could see methyl form of your prodrug in the system.
But still,your phenomenon of drug being a P-gp substrate and its
prodrug form being a P-gp inhibitor is not convincing.
I forsee your valuble comments
From
Ravi Kanth Bhamidipati
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