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I have a conceptual question. Is it possible to have a drug with a
low hepatic extraction ratio that is still completely metabolized by
the liver? If so, do you know of any specific examples of clinically
used drugs that exhibit this behavior, and any literature references?
Regards,
Alan Myers
Drake University
Des Moines, Iowa
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Many, Many compounds. Diazepam and warfarin are simple examples.
You don't need references just look them up in G&G
Leslie Z. Benet, Ph.D.
Professor
Department of Biopharmaceutical Sciences
University of California San Francisco
533 Parnassus Avenue, Room U-68
San Francisco, CA 94143-0912
Email: leslie.benet.-a-.ucsf.edu
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Alan:
The percent of a drug that is metabolized by the liver has nothing to
do with the hepatic extraction ratio, E.
A drug can be 100% hepatically metabolized, amd still have a hepatic
extraction ratio (E) that approaches 0, ie warfarin.
E is a measure of how efficiently the liver metabolizes that portion
of the dose that is hepatically eliminated. What confuses people is
that you can have a drug that only 10% hepatically metabolized, and it
may have an E = 0.8!!
Percent metabolized by the liver(or % renally excreted unchanged,
or ...some other clearing organ) is simply an estimate of the percent
of the dose eliminated via that pathway, it has nothing to do with the
efficiency of that pathway.
See any good PK text, or the articles on hepatic clearance by Rowland
and Tucker or Wilkinson.
--
William R. Wolowich, Pharm.D.
Chair
Department of Pharmacy Practice
College of Pharmacy
Nova Southeastern University
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The following message was posted to: PharmPK
Alan,
I assume you mean "completely" metabolized by the liver as drugs having
negligible urinary excretion and "low" hepatic extraction ratio as
less than
30%.
The best examples I am aware of are Tolbutamide, Phenytoin,
Carbamazepine,
Chlordiazepoxide, and Diazepam.
Cheers
SHAWN SPENCER, PhD.
Assistant Professor of Biopharmaceutics
Dyson Bldg., Rm 227
College of Pharmacy and Pharmaceutical Sciences
Florida A&M University
Tallahassee, FL 32307
shawn.spencer.-at-.famu.edu
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antipyrine is the best example.
Jasper Dingemanse
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Dear William,
You wrote:
> What confuses people is
> that you can have a drug that only 10% hepatically metabolized, and
> it may have an E = 0.8!!
You are right to make such a statement, but without further
explanation this will not be helpful for the 'confused people'.
I can imagine two situation where this could be the case:
1) The drug is metabolized in plasma (e.g. succinylcholine and
mivacurium by plasma cholinesterase) or is degraded spontaneously in
plasma (e.g. atracurium by Hoffman elimination). The clearance of such
a drug should be very high, at least 10 liters/min, because the
hepatic clearance is about 1 liter/min.
2) The drug is excreted efficiently into bile, i.e. most of the drug
taken up by the liver is excreted into bile, does not undergo
enterohepatic circulation, and is excreted into faeces or degraded in
the gastrointestinal tract.
Both situations seem to be rather uncommon, but not impossible, at
least theoretically. Also, a combination of #1 and #2 would be
possible.
My question is now:
a) Do you have examples of such drugs?
b) Are there other situations where a drug is only 10% hepatically
metabolized, and has an E = 0.8?
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
Email: j.h.proost.aaa.rug.nl
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The following message was posted to: PharmPK
Dear Hans,
You said:
"2) The drug is excreted efficiently into bile, i.e. most of the drug
taken up by the liver is excreted into bile, does not undergo
enterohepatic circulation, and is excreted into faeces or degraded in
the gastrointestinal tract."
How would one explain molecules of the parent drug being returned to the
intestinal lumen (in the duodenum) via biliary secretion, yet those drug
molecules would not be absorbed like molecules from the original dose?
In
other words, wouldn't there always have to be enterohepatic
circulation for
parent drug secreted back to the lumen in bile?
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.aaa.simulations-plus.com
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Dear Walt
The original question didn't specify po ...
"I have a conceptual question. Is it possible to have a drug with a
low hepatic extraction ratio that is still completely metabolized by
the liver? If so, do you know of any specific examples of clinically
used drugs that exhibit this behavior, and any literature references?"
regards
David
--
David Turner, PhD
Principal Scientist - Modelling and Simulation
Simcyp Limited
Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK
www.simcyp.com
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David,
I didn't save the original question, so I don't remember now if iv was
specified. Since most drugs are dosed orally, I assumed po.
Thanks,
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.-a-.simulations-plus.com
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The following message was posted to: PharmPK
Dear Walt,
Thank you for your comment:
> How would one explain molecules of the parent drug being returned
to the
> intestinal lumen (in the duodenum) via biliary secretion, yet those
drug
> molecules would not be absorbed like molecules from the original
dose? In
> other words, wouldn't there always have to be enterohepatic
circulation
> for parent drug secreted back to the lumen in bile?
There may be two situations:
1) Administration by intravenous (or, e.g.m intramuscular) route. In
this
case the oral availability of the drug is likely to be very low since
the
drug is not absorbed from the GI tract. Please note that the original
question, and my comment, did not deal with the route of administration.
2) If absorption occurs only in the first part of the duodenum, before
the
site where the bile enters. This might be a theoretical possibility
only; I
doubt whether this may be realistic. Any comments are welcome here.
best regards,
Hans Proost
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.-at-.rug.nl
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The following message was posted to: PharmPK
> How would one explain molecules of the parent drug being returned to
the
> intestinal lumen (in the duodenum) via biliary secretion, yet those
drug
> molecules would not be absorbed like molecules from the original
dose?
In
> other words, wouldn't there always have to be enterohepatic
circulation
> for parent drug secreted back to the lumen in bile?
Other possibilities for less extensive reabsorption of
parent drug after oral dosing could include situations where
the initial fraction absorbed was dependent upon;
a) saturation of first pass metabolism or efflux transport
by high intestinal concentrations after dosing
b) sensitivity to formulation
c) sensitivity fed/fasted state
With multidrug combinations there's also the possibility
of one drug being excreted in bile in the absence of a
co-dosed agent that could affect absorption.
All the very best,
Bernard
Bernard Murray, Ph.D.
Senior Research Scientist, Drug Metabolism
Gilead Sciences, Foster City CA
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The following message was posted to: PharmPK
Dear Bernard,
You noted:
"Other possibilities for less extensive reabsorption of
parent drug after oral dosing could include situations where
the initial fraction absorbed was dependent upon;
a) saturation of first pass metabolism or efflux transport
by high intestinal concentrations after dosing
b) sensitivity to formulation
c) sensitivity fed/fasted state
With multidrug combinations there's also the possibility
of one drug being excreted in bile in the absence of a
co-dosed agent that could affect absorption."
These are excellent points. But if the drug was originally absorbed
orally,
it seems there should still be some extent of reabsorption. Another
effect
could be when drug that is solubilized in the fed state is not
reabsorbed
well in the fasted state later on due to solubility limitations rather
than
permeability.
I think the most likely reason for absolutely no reabsorption when a
parent
molecule is secreted in bile is that is was dosed via another route to
begin
with and has essentially no intestinal solubility and/or permeability
or it
breaks down in the intestinal environment.
By the way, let's keep in mind that the word "absorption" has a very
specific modern meaning - entering the enterocytes. Not necessarily
reaching
the portal vein, and certainly not necessarily reaching the systemic
circulation, as it has been used in older publications.
Best regards,
Walt
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.aaa.simulations-plus.com
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