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The following message was posted to: PharmPK
Dear readers,
Which PK parameter would show the contribution of fecal elimination
of the drug to its total clearance from body?
Does elimination in the feces only affect the F value and not the
total clearance from body?
Thank you
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[Two replies - db]
From: Nick Holford
Date: Wed, 19 Dec 2001 07:14:06 +1300
To: david.at.boomer.org
Subject: Re: PharmPK
The following message was posted to: PharmPK
"panteha khalili (by way of David Bourne)" wrote:
> Which PK parameter would show the contribution of fecal elimination
> of the drug to its total clearance from body?
> Does elimination in the feces only affect the F value and not the
> total clearance from body?
Estimation of clearance from plasma concs alone cannot give any
direct information about any route of elimination. However, most
drugs that are orally absorbed can be expected to have some clearance
back into the gut and some fraction of the dose moving back into the
gut will be eliminated.
Activated charcoal binds drug in the gut lumen and can substantially
enhance net elimination by gut clearance for some drugs e.g.
theophylline. This is reflected in an increase in total clearance
estimated from plasma concs and accompanied by a decrease in
half-life.
--
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
---
From: David Jaworowicz
Date: Wed, 19 Dec 2001 09:43:33 -0500
To: david.-at-.boomer.org
Subject: Re: PharmPK PK parameters and fecal elimination
It depends upon your route of administration. If dosing orally, then
elimination in the feces can be solely due to incomplete absorption
(which only contributes to a decreased F), but there's also the
possibility of biliary excretion. If dosing is parenteral and then you
see drug in the feces, this is evidence for biliary excretion; this
process does contribute to total clearance of drug.
Typically, large molecular weight (>500), polar compounds can undergo
biliary excretion. The drug (or its metabolite) is excreted in bile and
enters the GI tract, where it can either be eliminated or possibly
undergo reabsorption (i.e. enterohepatic circulation). A common example
of the latter are glucuronidated compounds which can be converted back
to the parent compound by glucuronidases in the intestinal tract and the
parent can be reabsorbed. If you dose large enough amounts of drug
orally, you may see evidence of this as secondary peaks in plasma
concentration after Cmax.
Biliary cannulations in experimental animals for bile sampling is an
effective way to determine the extent that biliary excretion contributes
to the overall elimination of compound.
Sincerely,
David Jaworowicz
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The following message was posted to: PharmPK
>It depends upon your route of administration. If dosing orally, then
>elimination in the feces can be solely due to incomplete absorption
>(which only contributes to a decreased F), but there's also the
>possibility of biliary excretion. If dosing is parenteral and then
you
>see drug in the feces, this is evidence for biliary excretion;
The effect of P-glycoprotein can not be ignored in such cases. If the drug
is seen in the feces after IV administration, biliary excretion is not the
only route of elimination, but P-glycoprotein effect may be there. Alex et
al. studied the effect of P-glycoprotein on paclitaxel excretion after oral
and IV administration. They found 40% of the dose was excreted in feces
after IV administration in wild type mice. Whereas it was 3% in
P-glycoprotein deficient mice!!!
"Limited oral bioavailability and active epithelial excretion of paclitaxel
(Taxol) caused by P-glycoprotein in the intestine"
Alex Sparrebom et al. Proc. Natl. Acad. Sci 94:2031-2035 (march 1997)
Sreenivasa Rao Vanapalli, Ph.D.,
Janssen Postdoctoral Research Scholar,
S411 PHAR, College of Pharmacy, Univesrsity of Iowa,
Iowa City, IA-52242
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There is no good evidence from controlled studies that drug clearance
is enhanced by activated charcoal when it is administered more than
one hour after drug ingestion.
See: Green R et al. J Tox Clin Toxicol 39(6):601-5, 2001
Mayer AL et al Arch Intern Med 152:393-396, 1992
D. Sitar, University of Manitoba
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Dr. Vanapalli,
Your accurate assessment that P-glycoprotein may play a strong role in fecal
excretion prompts an additional question. What "populations" of P-glycoprotein
are the main source mediating fecal excretion? I'm aware that
P-glycoprotein is
located on the luminal side of areas in the gut, but P-glycoprotein has also
been identified on the apical surfaces of biliary ducts and at the biliary
canalicular front of hepatocytes. I would assume that these PGPs would
facilitate increased biliary excretion. In the paper you cited, did
the authors
explain how they distinguished between direct secretion into the gut lumen by
intestinal PGP versus PGP-mediated biliary excretion? I'm just wondering since
paclitaxel is a fairly large compound (MW>850).
Given my limited knowledge about P-glycoprotein, any comments would be greatly
appreciated.
Thanks a lot,
Dave Jaworowicz
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