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Dear all:
this may be a FAQ, but nonetheless: I am looking for any source of
bioavailability values for common drugs, if possible linked to the
chemical structures, in electronic form. So far my searches have been
unsuccessful. If you know of such resource, I would appreciate a
pointer.
Thank you!
VM
Vladimir Makarov
Scientist
BionomiX, Inc.
1055 East Colorado Blvd. #550
Pasadena, CA 91106
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I can't help but guess why you want such information, and I apologize
in advance if I am guessing wrong.
Since bioavailability is not a function of structure alone (ask any
formulation person - they can often change bioavailability by
changing formulation - with the same structure - by changing particle
sizes, excipients, using salt forms, etc.), I hope you don't intend
to make the all-to-common and misleading mistake of fitting a
bioavailability-to-structure model.
I say this in this tone because it amazes me how many I've met around
the world who want to do just that.
Because oral bioavailability depends on absorption (crossing the
apical membrane of the enterocytes), and because absorption is
dependent on a complex interplay of a number of variables that are
not dependent on structure alone, it is misleading to think one can
predict absorption or bioavailability from structure alone. Dose is
also important in many cases - a small dose might have good
bioavailability, while a large dose may not - or vice versa!
Can one fit such a model to a set of data? Sure, but what do you have
- a mathematical relationship for that set of data that almost tells
you what you already know. Is it useful for screening new compounds?
I would not use it that way, because it would probably reject some
compounds that would have adequate bioavailability with a little
formulation work, and it might keep others that are irreparably poor,
but whose similar compounds in the training set were good because
they did respond to formulation changes.
I think models that try to predict fraction absorbed or
bioavailability from structure alone may provide some degree of
insight into structural characteristics that can affect either, but I
believe that using them for screening purposes cannot be justified.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-a-.simulations-plus.com
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As a formulation scientist I fully agree with Walt's analysis.
Some parameters (dose administered, particle shape, particle size,
solubility, ...)are so much involved in absorption that we perform different
studies to ensure the linearity of PK parameters in a dose range and to
evaluate the impact of particle shape and size on the dissolution rate
influencing the absorption process as well.
Regards,
Frederic
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I can not agree more, want to add that we are running bioavailability
studies for some of the old drugs (danazole, ketoconazole) just by changing
the size (nanosizing) and comparing different nanosizing methods with
original (microsized) formulations by measuring plasma AUC as a parameter
for bioavailability. We are not only seeing higher AUC for nanosized drug
crystals but also for the method (technology) of nanosizing.
Shakil A. Saghir, M.S.P.H., Ph.D.
Senior Research Toxicologist
The Dow Chemical Co.
1803 Bldg., Midland, MI 48674
Email: ssaghir.-a-.dow.com
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Shakil,
I am not sure I understand well. Don't you agree with my previous message ?
I think that what you point out is not in disagreement with what Walt's and
I said. Absorption (after oral dosing) is known to be following a
dissolution step in the GI tract. The concern is that dissolution involves a
set of different elementary parameters such as solubility, solid state,
particle size and shape, etc... Differences observed between micro- and
nano- particles could probably be explained by the particle size. But the
difference observed between particles manufactured using different
nanosizing technologies should be explained by variations in the solid
state. How do you check that your different materials are physically
comparable (amount of amorphous particles for instance) ?
Cheers,
Frederic
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)