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I have the following queries:
1)If a drug has poor bioavailability in solution on oral
administration, but does not get metabolised, what are the
possibilities and are there simple ways of including/eliminating them.
2)would you have any suggestion for devising a simple
experiment where if the release is slowed (for e.g. would a CMC
suspension do it), and the bioavailability is compared to that of
oral solution, an improvement would give some idea of whether a
gastro-retenetive formulation would improve bioavailability.
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The following message was posted to: PharmPK Deepa,
The answers to your questions lie in a complex interaction of
processes including transit, solubility/dissolution/precipitation,
absorption, and possibly pharmacokinetics. These things can be
investigated by simulation - if you have enough data on your compound.
If you dose as solution and have poor bioavailability (you did not
say how "poor" it is), it could be due to:
(1) low permeability in small intestine and/or colon
(2) precipitation and slow redissolution
(3) degradation of the drug in the intestinal lumen
(4) unexpected gut metabolism (are you sure the drug is not
metabolized? How is it cleared - renal only as parent drug?)
(5) any combination of the above
The ideal amount of data to investigate the possibilities would be
(assuming the drug is not metabolized):
(1) physicochemical properties:
(a) solubility at specified pH in physiological fluids
(c) logP or logD .-at-. specified pH
(2) some measure of permeability
(3) extent of protein binding in plasma
(4) dose and formulation
(5) IV and oral plasma concentration-time data in the same subjects/animals
Physicochemical properties and permeability can be estimated using in
silico methods; however, experimental data are always preferred.
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
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[Two replies - db]
From: "Doc, Frederic"
Date: Tue, 4 Jun 2002 05:32:06 -0400
Subject: RE: PharmPK
1- as long as I think of your concern, I should suggest the same as Walt
Woltosz (Hi Walt. How are you ?). But I should add the existence of an
absorption window in the GI tract. Your solution should not be kept in the
absorption area for a long time and absorption should therefore be limited.
What is the formulation used for animal dosing ? pH ?
2- If your compound does not have any solubility issue I am pretty sure that
a CMC suspension is not the right formulation in order to get a sustained
release effect. In the GI tract the CMC suspension won't provide your
compound with any protection. Therefore your compound will solubilize and
you'll be back to something that looks like a dosing solution.
On a formulation point of view the interaction between your active and an
ingredient should be more important than just a dispersion of the powder in
a solution of CMC. What I suggest is that you consider the opportunity to
develop a solid dispersion or dry granules to be dispersed as oral
formulations. I did this kind of work with some success some months ago.
PFIZER Global R&D
From: "ogwal sidney"
Date: Tue, 04 Jun 2002 15:05:45 +0000
Subject: Re: PharmPK Poor oral bioavailability
When a drug has poor biovailability upoon oral administration there is
absolutely no simple experiment one can design to improve the Biovaila
bility. Go back to the factors that affect Biovailability.
However if it is due to poor formulation check the following:
Your compression force used in tabletting if the drug in question is
a tablet well you didn't specify the dosage form
Method of preparing the granulation.If it is a tablet there are three
methods: wet,dry granulation and direct compression. Did you select
the appropiate method to prepare your tablet.
Check the effect of excipients or adjuncts on your formulation.ie
binders,moistening agents,diintergrating agents etc on the formulation
Are all the ingredients you used in the formulation compatible
Check all the Physiochemical properties of your active ingredient
and find out whether it is compatible with the other excipients in
your formula.Check the method of analysis you are using and the calcul
ations is it correct.
However the primary cause of poor biovailabilty is poor formulation
Lecture in Pharmaaceutics Department of Pharmacy
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