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The following message was posted to: PharmPK
Dear readers,
I just came across an example in an introductory pharmacokinetic book
about "flutamide". Based on this example, the compound is 90%
metabolized and completely absorbed (F=1).
How is it possible to have so much metabolism and yet F=1?
Shouldn't the amount of metabolites(%)roughly be equal to 1-F?
Thank you for any clarifications.
[The latest worm has disrupted email (again) so there is a little
backlog on the PharmPK list. I'll try combine similar topics and send
out a few messages a day until things are more 'normal'.
Re this post - is all/most of the metabolism in the liver? - db]
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[Three replies - db]
From: David Jaworowicz
Date: Thu, 20 Sep 2001 18:30:22 -0400
To: david.aaa.boomer.org
Subject: Re: PharmPK Re: Metabolism and bioavailability (absolute)
Theoretically, a drug that undergoes extensive metabolism can still
exhibit a bioavailability (F) that approaches 1. This can be seen in
the case of low-extraction drugs in which the extraction ratio (ER) is
very small due to high protein binding and a very low intrinsic hepatic
clearance, according to the equation:
ER = (fu*CLint)/(Q+CLint*fu) where fu is fraction unbound and Q is liver
blood flow
and
F = 1-ER
Furthermore, metabolism could be in other organs, not just liver.
Just as an aside note, for an orally administered compound,
bioavailablity (F) and absorption should be properly distinguished from
one another. A drug that undergoes complete absorption can still have a
bioavialability less than 1. Oral absorption is technically the net
movement of drug from the lumen of the GI tract into the blood (i.e.
portal vein) while F is the fraction of administered drug that actually
reaches the systemic circulation.
Also, the % metabolites does not = 1-F due to other factors such as
incomplete absorption and/or degradation within the GIT, metabolism
elsewhere in the body. This equation is only true for the very first
pass of an oral drug that does not undergo any GIT degradation or fecal
excretion, with 100% of administered drug being subject to gut and/or
hepatic metabolism.
---
From: "Stephen Duffull"
Date: Fri, 21 Sep 2001 09:05:24 +1000
To: david.aaa.boomer.org
Subject: RE: PharmPK Re: Metabolism and bioavailability (absolute)
The following message was posted to: PharmPK
If we ignore absorption for the time being - and just concentrate on
first-pass metabolism then it is quite possible to have a drug that is
extensively metabolised and has low first-pass metabolism (eg warfarin),
ie high bioavailability. The degree of first pass loss is related to
the CL of the drug (not how the drug is cleared).
Since we know CL=Q*E (Q=perfusion, E=extraction ratio) then you will
find that
F [is approximately] =1-E where
E [is approximately] = CL/Q.
Regards
Steve
Stephen Duffull
School of Pharmacy
University of Queensland
Brisbane, QLD 4072
Australia
Ph +61 7 3365 8808
Fax +61 7 3365 1688
http://www.uq.edu.au/pharmacy/duffull.htm
---
From: "Hans Proost"
Date: Fri, 21 Sep 2001 14:28:08 MET
To: david.aaa.boomer.org
Subject: Re: PharmPK Re: Metabolism and bioavailability (absolute)
The following message was posted to: PharmPK
Dear Dr. Khalili,
If a compound is 90% metabolized and bioavailability is complete,
hepatic clearance is 90% of total clearance; the remaining 10% is
probably renal clearance. This does not necessarily mean that
clearance is high. For example, a drug with high plasma protein
binding and/or extensive reabsorption in the kidney may have a low
renal clearance. Although hepatic clearance is about 9 times
higher than renal clearance, it still may be low, resulting in low
extraction. As a result, F may be close to 1, and thus
bioavailability may be virtually complete.
Sincerely,
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.aaa.farm.rug.nl
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The following message was posted to: PharmPK At 02:12 PM 9/21/01
-0500, David Jaworowicz wrote:
>...... Oral absorption is technically the net
>movement of drug from the lumen of the GI tract into the blood (i.e.
>portal vein) while F is the fraction of administered drug that actually
>reaches the systemic circulation.
>
This is not the definition of absorption we use. It used to be, but I
think there is now a consensus that absorption is defined as crossing
the apical membrane (in the absence of paracellular transport).
Thus, we consider the drug to be absorbed when it leaves the lumen
and crosses the apical membrane into the enterocytes, not when it
reaches the portal vein. If there is no gut metabolism, then there is
little difference (the difference would be the accumulation of drug
in the enterocytes); however, consider midazolam, which is
extensively metabolized by 3A4 in both gut and liver. Gut metabolism
of midazolam is about the same as liver metabolism during the
absorptive phase. About 30% of the midazolam that crosses the apical
membrane is metabolized in the enterocytes, so only about 70% of the
absorbed drug reaches the portal vein. So the drug could be 100%
absorbed, with 70% reaching the portal vein, and 40% reaching the
systemic circulation.
Since it is estimated that a significant percentage of all drugs are
metabolized by 3A4 and/or other gut enzymes, it is important to be
able to distinguish absorption from drug reaching portal vein and
from bioavailability.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
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