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All,
I'm seeking insights in this question. Suppose some receptor in the
intestinal muscle layers is my target. After oral dosing, does the
receptor see the drug molecules before the molecules hit the portal
and systemic circulation or after the molecules are transported back
to the receptor by the systemic circulation? The argument for the
former is that there is concentration gradient between the blood
underneath the villi and the receptor. However, the counter-argument
is the molecules may not travel down the gradient given the fact that
the villi and muscle are perfused by different microvessels.
Put this question into context. For the effect elicited by activation
(or antagonism) of the receptor, do we expect to see different effect
profiles after oral and subcutaneous dosing given the systemic
exposure profiles are maintained to be the same?
I tried to get some publications on these issues, but no luck so far.
If you could suggest some references, I'd highly appreciate it.
Thanks,
Yasong Lu
--
Yasong Lu
Translational Research Group
PDM, PGRD
Groton/New London Laboratories
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The following message was posted to: PharmPK
There is no reason to believe that a drug would stop diffusing from
the gut
at the submucosa and not diffuse into the muscularis. That being
said, the
richness of vessels in the submucosa may act as a sink for the drug,
reducing the amount reaching the muscularis.
Could you be so kind as to complete and return the survey I sent out
earlier?
Thank you.
Edward F. O'Connor, PhD
78 Marbern Drive
Suffield, CT 06078
efoconnor.at.cox.net
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he following message was posted to: PharmPK
Dear Dr. O'Connor,
Your post implies that there was an earlier one on the same subject. I
must
have missed it. I don't remember a survey.
This is an issue we've thought about for years, but have not been able
to
come to any conclusions. Clearly, the muscularis has the potential for
receiving drug both from the submucosa as well as from its own blood
perfusion. However, as you noted, the richness of the vasculature in the
submucosa probably gets most of what is absorbed from the lumen (by
design),
so perhaps the major source of drug for the muscularis is distribution
from
its own perfusion.
If anyone has any data (rat?) regarding this, we'd love to see it.
Best regards,
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.-at-.simulations-plus.com
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The following message was posted to: PharmPK
Yes, there is evidence for the submucosa acting as a sink for a drug.
In high resolution autoradiograms with 3H-1,25 (OH)2 vitamin D3 we see
concentration and retention in the submucosa of the stomach and
intestine, demonstrated in "Vitamin D and the digestive system"
published in European Journal of Drug Metabolism and Pharmacokinetics
33[2008] (2),85-100.
Walter E Stumpf, Dr.med., Ph.D.
2612 Damascus Church Rd
Chapel Hill, NC 27516
www.walterstumpf.com
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The following message was posted to: PharmPK
If I may add a different perspective, I suspect the degree of muscularis
"primary-level" distribution is likely not drug-independent. So,
perhaps
its best to first pose the question, "is the drug distribution..
perfusion
or permeability limited?", and devise a model accordingly.
I would suspect although a relatively polar or large drug may have
negligible muscularis uptake and clearance independent of mesenteric or
splanchnic flow and concentration,...the more non-polar compounds should
have significant concentration dependent primary access to the
intestinal
muscle receptors (via a saturated submucosa in some cases), prior to
secondary muscle perfusion. Although the submucosa can retain perhaps
many
compounds, it probably acts much like a chromatography column, allowing
certain drugs to pass through faster than others.
With regards to the effect, I would attempt to model pre-clinically, the
effect of ROA,... SQ, IV, and Oral Gavage, and the differences in the
AUEC
or "effect exposure" should tell you the general degree of primary-level
distribution for drugs with that degree of polar surface area.
Of course, this is all "in theory".
Regards to all,
Shawn D. Spencer, Ph.D., R.Ph.
Assistant Professor of Biopharmaceutics
Florida A&M College of Pharmacy
Tallahassee, FL 32307
shawn.spencer.-at-.famu.edu
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