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I have a molecule which is quite rapidly metabolised in blood and most
other
tissues (with metabolites found in urine and bile), and is also
metabolised
within the gut. How could I design a study to estimate gut absorption
of
this molecule from an oral dose? From plasma data it would be hard to
distinguish metabolism in the body from that in the gut, and so gut
absorption would be very poorly specified. Could I estimate gut
absorption
from the difference in results from an oral and from an iv dose? I
suppose
even this would be hard due to the confounding effect of first-pass
liver
metabolism. Has anyone had the same problem? Any thoughts appreciated,
Kim Travis
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The following message was posted to: PharmPK At 07:47 AM 1/29/2004, Kim
Travis wrote:
"
I have a molecule which is quite rapidly metabolised in blood and most
other
tissues (with metabolites found in urine and bile), and is also
metabolised
within the gut. How could I design a study to estimate gut absorption
of
this molecule from an oral dose? From plasma data it would be hard to
distinguish metabolism in the body from that in the gut, and so gut
absorption would be very poorly specified. Could I estimate gut
absorption
from the difference in results from an oral and from an iv dose? I
suppose
even this would be hard due to the confounding effect of first-pass
liver
metabolism. Has anyone had the same problem? Any thoughts appreciated,
"
This type of analysis has been accomplished with GastroPlus(tm). It is
not simple, but it can be done if you have the right data. That's where
the study design comes in. To deduce the gut metabolism, it would be
helpful to have:
(1) physicochemical properties (solubility-pH, pKa(s), logP, plasma
protein binding, blood/plasma concentration ratio, chemical stability,
etc.)
(2) in vitro permeability of some kind
(3) iv plasma concentration-time data at concentrations similar to
those encountered in oral doses
(4) oral plasma concentration-time data at more than one dose
(5) metabolism in microsomes or hepatocytes (Vmax and Km - not just
turnover)
(6) if possible, specific isozyme metabolism data would be ideal (3A4,
2D6, etc.)
If your compound is being metabolized only by 3A4 or 2D6, it should be
easier, because the distributions of these enzymes in gut is known. If
other metabolic pathways are significant, then a bit of detective work
is required to separate the gut and liver metabolism. The trick is to
find a single nonlinear model that fits all doses - if the model has to
be changed for different dose levels, then something's wrong.
If you can fit a single structural model that explains all doses, then
you have ausefulmodel within the range of concentrations covered by
your data (remember, as Box says, "All models are wrong, some models
are useful").
Feel free to call or e-mail if you need help.
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.-a-.simulations-plus.com
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Dear Walt,
You can sample from the portal vain after dosing. See the ref. J.
Pharmacy
and Pharmacology 2001, 53: 901-906.
R. C. Gupta
Pharmacokinetics and metabolism Div
CDRI
Lucknow
India
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Hello,
the use of the radiolabelled drug in bile duct cannulated rats allows
the
calculation of the extent of absorption by determination of the total
radioactivity excreted in bile and urine.
regards
Markus
Dr. Hans Markus Bender
Merck KGaA
Institute of Drug Metabolism and Pharmacokinetics
Am Feld 32
D-85567 Grafing
[Germany]
Tel: 08092 / 7008-14
Fax: 08092 / 7008-99
e-mail: hansmarkus.bender.aaa.merck.de
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Dear Kim,
There are two possible solutions here;
Sample blood from the portal vein.
Use a perfused small intestine model in which the circulation to all
organs apart from the small intestine is tied off. The in-situ isolated
intestine is then perfused via the mesenteric artery with the effluent
being collected from the hepatic portal vein. This type of preparation
has been used very successfully to look at gut metabolism and can be
used in both first pass and recirculating modes. You can even use a
tandem system sampling from the portal vein and then directing the
remainder of the effluent into an isolated perfused liver. In this way
the contribution of both organs can be assessed.
I would refer you to 'Models for Assessing Drug Absorption and
Metabolism' Edited by Ronald T. Borchardt, Philip L. Smith and Glynn
Wilson, Plenum Press 1996 which has a lot of useful information in it
plus very comprehensive lists of references at the end of each chapter.
Hope this helps,
Nick Kerwin
Head of In-Vivo Discovery
BioDynamics Research Limited
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At 07:29 PM 1/29/2004, are C Gupta wrote:
"You can sample from the portal vain after dosing. See the ref. J.
Pharmacy
and Pharmacology 2001, 53: 901-906."
Can you do this in human? I know this has been done in animals, but it
was my understanding that it is not done in human.
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.aaa.simulations-plus.com
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[Doug Ridgway]
See Clin Pharmacol Ther. 60(1): 14-24 1996 for one study in human. The
subjects were undergoing liver transplantation.
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I would suggest starting some in-vitro stability studies of your drug
using freshly
aspirated intestinal fluids from humans.
Nasir Idkaidek,Ph.D.
Head of Clinical Studies
Triumpharma Ltd
Jordan
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