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The following message was posted to: PharmPK
Hi there
how is everyone?
i have a question,
what is the role of the first pass effect in low-dose aspirin?
what is the point of using low dose aspirin? other than to reduce GI
irritation? how does this low dose work to reduce the first pass
metabolism , compared to effect of high dose?
please excuse my lack of knowledge, this is our first year in studying
biopharmaceutics!
hope someone is able to fill me in. =)
thanks,
linda
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The following message was posted to: PharmPK
Linda,
My understanding is that, following oral administration, aspirin binds
irreversibly to the cyclo-oxygenase of the platelets in the portal
circulation. As the blood passes through the liver, the bound aspirin is
unavailable for metabolism, whereas the unbound aspirin (small amounts,
due
to the low dose), is metabolized. This explains the fairly long
duration of
action (aspirin essentially remains bound to the cyclo-oxygenase for the
'life-span' of the platelet) as well as the lack of systemic
side-effects
with this dosage regimen.
Perhaps others on the list have further details on the mechanism.
Ronette Gehring
Ronette Gehring, BVSc MMedVet (Pharm)
Research Assistant Professor of Pharmacology
Food Animal Residue Avoidance Databank
Center for Chemical Toxicology Research and Pharmacokinetics
College of Veterinary Medicine
North Carolina State University
Raleigh
NC 27606
Tel: (919) 513-6803
Fax: (919) 513-6358
888-USFARAD (FARAD)
E-mail: Ronette_Gehring.aaa.ncsu.edu
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The following message was posted to: PharmPK
Linda, see this reference.
FitzGerald GA. Lupinetti M. Charman SA. Charman WN. Presystemic
acetylation
of platelets by aspirin: reduction in rate of drug delivery to improve
biochemical selectivity for thromboxane A2. [Journal Article] Journal of
Pharmacology & Experimental Therapeutics. 259(3):1043-9, 1991 Dec.
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The following message was posted to: PharmPK
aspirin does not bind to cyclooxygenase-1 but it acetylates this
protein,
mainly in the presystemic circulation. The remaining aspirin is partly
deacetylated in the liver to salicylic acid. The intact aspirin that
escaped the first pass deacetylation is available to acetylate
COX-enzymes
in other parts of the body, for example in the mucosa of the stomach and
the endothelium of blood vessels.This may cause side effect by
decreasing
the production of prostacylin
The best therapeutic ratio between the (intended) reduction of
thromboxane
and the (not intended) reduction of prostacyline will be achieved if all
absorbed aspirin is deacetylated by platelet-cyclooxygenase and nothing
remains to acetylate cyclooxygenase in other parts of the body.
Theoretically the best way to achieve this goal is the use of the lowest
effective dose of aspirin in a slow release form.
In the Dutch TIA trial it has been shown that aspirin 30 mg daily is as
effective as 300 mg daily in the secundary prophylaxis of CVA. In a
recent
trial we found that aspirin 30 mg daily for 10 days reduced serum
thromboxane with 92%, so this appears to be enough for effective
thromboprofylaxis.
Higher doses appear not to cause better thromboprophylaxis and entail
the
risk to achieve worse results because of stronger suppression of other,
useful prostaglandines such as prostacyclin.
This may explain why 80 or 160 mg aspirin once daily was significantly
more
effective than 625 or 1250 mg once daily in patients with carotis
surgery.
Moreover in a recent meta-analysis it was found that there is an
interaction between aspirin and the efficacy of ACE-inhibitors if the
dose
of aspirin is higher than 160 mg daily.
Hans Vollaard
YuHan Kho
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)