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I've read that it is possible to measure the fraction
of drug absorbed following a p.o. dose (i.e., F) by
dosing radioactive compound both i.v. and p.o. and
comparing total radioactivity excreted in the urine.
This can be a useful way to indirectly assess first
pass metabolism (when systemic bioavailability is also
determined).
Does anyone have experience using this method and/or
references?
Also, does anyone know of a situation were this method
would *not* reflect F.
=====
Stephen Day
Merck-Frosst Centre for Therapeutic Research
Kirkland, QC CANADA
[Using different isotopes? - db]
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[A few replies - db]
From: Bernhard.Ladstetter.-a-.merck.de
X-Internal-ID: 38DDDBAC00021D29
X-Lotus-FromDomain: MERCK
To: PharmPK.aaa.boomer.org
Date: Thu, 6 Apr 2000 09:47:32 +0200
Subject: Antwort: PharmPK
Comparison of total radioactivity excreted in urine after iv and po gives you a
good estimate of extent of absorption if the elimination with urine is a major
route of excretion. To be on the save side you can do the same experiment in
bile duct cannulated rats by determination of total radioactivity excreted with
bile. Both experiments are part of the routine "mass balance"
experiments during
preclinical development.
Regards,
Bernhard J. Ladstetter, Ph.D.
Institute of Pharmacokinetics & Metabolism
Merck KGaA, Germany
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Date: Thu, 06 Apr 2000 08:04:25 -0400
From: "Cotler, Stanley {NCDS~Nutley}"
Subject: RE: PharmPK Measuring oral absorption
To: "'PharmPK.-at-.boomer.org'"
A reference for such a study is S Cotler, CJL Bugge and WA Colburn,
Drug Metabolism and Disposition, Vol 11 (5), 458-462, 1983
Stanley C
Stanley Cotler
Department of Non-Clinical Drug Safety
Phone (973) 235-2857 Fax (973) 235-7010
E-Mail Stanley.Cotler .-a-.Roche.com
Nutley
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Date: Thu, 6 Apr 2000 06:37:35 -0700 (PDT)
From: Stephen Day
Subject: Re: PharmPK Measuring oral absorption
To: PharmPK.-at-.boomer.org
I read about this in "Biopharmaceutics and Clinical
Pharmacokinetics" by Milo Gibaldi, p 138
.... The fraction absorbed may be determined from the
urinary excretion of drug and metabolites, usually as
total radioactivity, after oral administration of the
drug (in a radiolabeled form), relative to that after
intravenous administration...
clip
> I've read that it is possible to measure the
> fraction
> of drug absorbed following a p.o. dose (i.e., F) by
> dosing radioactive compound both i.v. and p.o. and
> comparing total radioactivity excreted in the urine.
It was late, I meant dosing different animals (not the
same animal both i.v. and p.o.)
clip
=====
Stephen Day
Merck-Frosst Centre for Therapeutic Research
Kirkland, QC CANADA
---
From: "Loewen, Gordon"
To: "'PharmPK.aaa.boomer.org'"
Subject: RE: PharmPK Measuring oral absorption
Date: Thu, 6 Apr 2000 08:07:57 -0700
Stephen;
Without bothering with all the equations, the easiest way to demonstrate
that the ratio of the % of dose excreted in urine following IV or PO
administration does NOT necessarily reflect the fraction of dose absorbed is
to consider an extreme situation.
Drug X: Extensively absorbed, but very rapidly metabolized to a metabolite
that is only excreted in bile (assume essentially 100% first pass). For
drug that does reach the systemic circulation (e.g., following an IV dose),
Dug X is also actively secreted in urine. Therefore, following an oral
dose, essentially 100% absorption, but 0% of the dose is excreted in urine
and 100% of the dose is excreted in bile as the metabolite. Following an IV
dose, because the drug is in the systemic circulation, there will be some
secretion/excretion of the drug in urine and some elimination of drug in the
bile (as the metabolite) - the ratio of which will be dependent on the
respective organ clearances. Obviously, in this instance, the ratio of % of
dose excreted in the urine following IV/PO dosing does not provide a
meaningful estimate of the percent of an oral dose that was absorbed.
Granted, this is an extreme example, but it does indicate that you cannot
ASSUME that the ratio is meaningful. Note that there may be instances where
the ratio might be correct (e.g., no hepatic metabolism/elimination), but
you just can't assume it is correct for all drugs.
Gord
---
X-Sender: jelliffe.-a-.hsc.usc.edu
Date: Thu, 06 Apr 2000 08:28:58 -0700
To: PharmPK.at.boomer.org
From: Roger Jelliffe
Subject: Re: PharmPK Measuring oral absorption
Dear Stephen:
About measuring the fraction of an oral dose absorbed. One can give a
patient or a subject a dosage regimen consisting of both oral and IV
administration. Administration by both routes, some doses IV, others PO,
will permit calculation of F. We use this approach in the USC*PACK programs
for population modeling using both the iterative Bayesian 2 stage approach
(IT2B) and the nonparametric (NPEM) method. There is no need for washout
between the 2 routes of administration. A dosage regimen consisting of a
combination of PO and IV routes will do the job, and without the
opportunity for parameter values to change nearly as much as they may
between two separate routes of administration with a washout period in
between. There is no need to do two separate studies, one IV and the other
PO, and to compare areas under the curves any more.
Hope this is useful,
Roger Jelliffe
---
From: "Jean-Pierre Guichard"
To:
Subject: Re: PharmPK Measuring oral absorption
Date: Thu, 6 Apr 2000 20:21:35 +0200
X-Priority: 3
If there is a biliary excretion of the radioactivity with incomplete
reabsorption, this method will underestimate the oral absorption.
Of course, if you measure only total radioactivity you will not assess
bioavailability but only absorption of radioactivity, except if the compound
is not metabolized.
Best regards
Jean-Pierre Guichard
Laboratoires Fournier
50, rue de Dijon
F-21120 DAIX
FRANCE
---
Subject: Re: PharmPK Measuring oral absorption
To: PharmPK.aaa.boomer.org
From: Varun_Garg.at.vpharm.com
Date: Thu, 6 Apr 2000 15:32:54 -0400
If the drug was metabolised or degraded in the gut and the product
absorbed, the po/iv ratio of radioactivity
would not reflect the fraction absorbed.
---
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Dear Stephen and List Members:
I think it may adequate to look at the problem more carefully.
The things well known are:
1) Radioactivity recovered in urine after p.o. reflects
fraction absorbed
if the drug and its metabolite are 100% excreted in urine.
2) Percentage of radioactivity (against dose) excreted in
urine after p.o. (%) is always smaller than fraction absorbed (%).
3) The sum of excretion in bile (i.e. in Bile duct cannulated rats)
and urine reflects fraction absorbed.
Here, the point is:
4) Does "COMPARISON" of radioactivity recovered in urine after
p.o. "AND I.V." provide insight for the fraction absorbed?
Let me present a example.
a) Drug A is 40% excreted in urine, 60% in feces (i.e., via bile) after iv.
After po, 20% excreted in urine, 80% in feces.
Is it adequate to guess that 50% of Drug A is absorbed?
I have a feeling that comparison of po and iv may enable us to estimate
fraction absorbed in many cases, but there would be some cases this method
does not work (for example, the drug is 100% excreted via bile).
As commented by Gordon, this mathod does not work also for the case of
100% hepatic first-pass effect.
I would like to think about this issue a little more.
I hope this comment contributes to the list.
Makoto Niwa,
Nippon Kayaku Co., Ltd.
e-mail:mniwa.-at-.nipponkayaku.gr.jp
URL:http://member.nifty.ne.jp/mniwa/
Tokyo, Japan
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)