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Hi all,
We are developing a new molecule exhibiting 100% orally bioavailability in
rats by oral route with 1hr half life. It shows peripheral target organ
toxicity at higher doses by oral route and not by IV route. Can any one
help me in understanding the possible reasons underlying this route of
administration dependent toxicodynamics.
thanks
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Hello Dr Paliwal
From what I understand
Toxicity due to a drug in an organ can result from what the drug directly does
in the organ and also from what the drug does to the other processes which
might influence the functionality of an organ. After high oral dose of your
drug you might be influencing the absorption, reabsorption of many vital
endogenous substances in the body. This effect might not be seen at lower doses
(I am guessing!). After intravenous dose the relative exposure of the git to
the drug will be less (unless your drug is extensively excreted in the bile).
So the toxicity might be a cumulative effect of all these. To rule out this
option I would suggest that if you could give the same dose intraperitonally
and check the same. Perhaps a toxicology expert can comment on this. Another
reason could also be that your drug might be irreversibly inhibiting the
enzymes in the git (which are known to detoxify many substances by their
metabolism). As a result the organs might be exposed to a greater amounts of
these unmetabolised substances which can trigger several events in organs like
liver and thereby result in toxicity.
I hope this helps.
Atul
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The following message was posted to: PharmPK
Sounds like a metabolite or salt effect to me, either an effect of stomach acid
or first pass metabolism.
Daniel M. Byrd III, Ph.D., D.A.B.T.
President,
Consultants in Toxicology, Risk Assessment and Product Safety
Suite N707
560 N Street, SW
Washington, DC 20024
(202)484-7707 - phone
(202)484-0616 - fax
ctraps.aaa.radix.net - email
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[Two replies - db]
From: "Kramer, Hester"
Date: Mon, 21 May 2001 09:22:49 +0100
To: david.at.boomer.org
Subject: RE: PharmPK Toxicity by oral route
The following message was posted to: PharmPK
Dear paliwal,
Just some quick toughts on this subject:
What was the vehicle that was used to administer the oral dose and the iv
dose? may be here you can find some explanation.
I recently read something about metabolism in the lungs after iv dosing.
This resulted in a lower bioavailability of the compound. However, general
practice is to use the iv dosing scheme to set at 100%. Although you find a
100 % bioavailability the after oral dosing, still some first pass
metabolism could occur but resulting "coincidentally" in similar AUCs as
that after iv dosing. Thus 100 % bioavailability. The difference in toxicity
could be explained by the formation of other metabolites by the one route
and by the other route: e.g. the enzyme composition in the lungs is
different from that in the gut and in the liver.
---
From: sunil bajad
Date: Mon, 21 May 2001 07:17:29 -0700 (PDT)
To: david.at.boomer.org
Subject: Re: Toxicity by oral route
The following message was posted to: PharmPK
Respected Dr. Paliwal,
Let me share my experience on the topic. I have
studied the metabolism of a highly lipophilic compound
with conjugated double bonds. The new metabolite
isolated from urine after oral administration is a
dihydro derivative of the parent molecule. The dihydro
and tetrahydro derivatives of the parent molecule have
been reported to have more potent drug metabolising
enzyme inhibitory activity. The minor change would
also make it difficult to separate these molecules by
HPLC making it difficult to determine the correct
plasma concentration time profile of the parent
molecule. A minor change in the basic structure caused
by liver or intestine could drastically change the
toxicity profile as well. In my opinion, the
lipophilic molecules are more susceptible to this kind
of change.
Though I am not sure but the molecule you are
studying should be a lipophilic one. I would suggest
you to go for LC/MS studies to identify the molecule
in plasma after oral administration.
Hope this is helpful.
Sunil
Research Associate
Pharmacology Division
Regional Research Laboratory
Canal Road, Jammu INDIA
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