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Hello to All:
I am trying to measure the distribution of a drug and its major
metabolite after p.o. administration in an adult male rat. I have picked
the apparent half-life after p.o. administration as my time point for
tissue collection since the plasma levels of both compounds are high. I
would like to know the total amount of drug and metabolite associated
with each tissue sampled with the intention of accounting for about 80%
of the dose administered (I have reason to think that very little drug
or metabolite is eliminated in the urine at this point though unabsorbed
drug is an important consideration). I have two questions for the group:
1. Does anyone know of a source for estimates of total muscle, skeleton,
fat and skin mass relative to body weight for the rat?
2. Does anyone have any experience in doing this kind of study? If so I
would like to correspond with you to better understand the potential
pitfalls involved.
Thanks in advance.
Richard Knapp, Ph.D.
Director of Pharmacology
Cortex Pharmaceuticals, Inc.
rknapp.at.cyberannex.com
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We have recently published a paper that you may find useful in which we
provide relative organ weight data for rats and other species (Brown,
R.P., Delp, M.D., Lindstedt, S.L., Rhomberg, L.R. and Beliles, R.P.
(1997) Physiological parameter values for physiologically based
pharamacokinetic models, Toxicol. Ind. Health, 13(4):407-484).
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[Quite a few replies -- some that I don't remember from the last time this
question was raised ;-) - db]
Date: Fri, 20 Mar 1998 08:24:50 +0100
From: Hans Markus Bender
Reply-To: HansMarkus.Bender.at.merck.de
Organization: merck.de
MIME-Version: 1.0
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Rat Organ Weights
Dear Richard Knapp,
we performe very frequently distribution studie in our Institute. For
exact mass balance & distribution one require the radiolabelled
compound.
An old source of portions of tissues in rats is: "Duhm et al.:
Tierexperimentelle Untersuchung zur Pharmakokinetik von radioaktivem
Propiramfumarat", Arzneimittelforschung 24/24a, 632-43, 1974.
muscle:40%, skin: 22%, fat 5%, bone marrow 4.5%.
A satisfying time point for dissection after oral dosing might be tmax.
If the distribution of unchanged drug is required, I would prefer
parenteral (iv, if possible) administration and dissection after 5 to 10
minutes. After oral administration I would recommend to determine the
amount of (possible unabsorbed)drug in the GI-tract separately if
detailed balance of the total dose is required.
You are wellcome for discussion of this topic!
Dr. Hans Markus Bender
Institute of Pahrmacokinetics and Metabolism
Merck KGaA
---
Comments: Authenticated sender is
From: xwang.aaa.mga.com
Organization: MGA Software
To: PharmPK.at.pharm.cpb.uokhsc.edu
Date: Fri, 20 Mar 1998 12:34:55 +0000
MIME-Version: 1.0
Subject: Re: PharmPK Rat Organ Weights
Priority: normal
There is a Report, Physiological Parameter Value for PBPK Models,
prepared by the International Life Sciences Institute Risk Science
Institute (cooperated with USEPA). In this Report, there are
physilological paramters such as body weight, cardiac output, blood
flow rate through each tissues, tissue volumes, tissue blood volumes
for lots of species (mice, rats, dogs, humans etc.) including
different strains.
> 2. Does anyone have any experience in doing this kind of study? If so I
> would like to correspond with you to better understand the potential
> pitfalls involved.
To study the absorption, distribution, metbolism, and excretion of
the parent compound and its metabolites in specific tissue, you have
to conduct physiological pharmacokinetic modeling (called PBPK
models).
Hope it helpful to you.
xiaofeng
***************************************************
Xiaofeng Wang, PhD Web: WWW.MGA.COM
Applications Scientist 508-369-5115
xwang.aaa.mga.com 508-369-0013 FAX
MGA Software, Inc.
200 Baker Ave.
Concord, MA 01742
***************************************************
---
Date: Fri, 20 Mar 1998 08:01:14 -0500
From: "Nabil B. Darwazeh"
To: PharmPK.-at-.pharm.cpb.uokhsc.edu
Subject: PharmPK Rat Organ Weights -Reply
Mime-Version: 1.0
Dear Richard
you may want to try the following ref:
The rat in laboratory investigation
E.J. Farris and J.Q. Griffith, Jr (Edrs)
I did similar work looking for the tissue distribution of radiolabled
polymers, but I did not separate muscles from bones.
For the rat organ weights, they are in Experimental and Surgical
Technique in the rat, H.B. Waynforth.
Please contact me I can be any help
good luck
Nabil B. Darwazeh, Ph.D.
Wyeth-Ayerst Research
Tel: 914-732-2173
darwazn.-at-.war.wyeth.com
---
From: "Michael Kohn"
Date: Fri, 20 Mar 1998 08:35:04 -0500
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Rat Organ Weights
Mime-Version: 1.0
On Mar 19, 2:26pm, "Richard Knapp"by way of David_Bourne wrote:
See my Web site at the URL
http://valiant.niehs.nih.gov/submodels/male_rat_phys.mod
for organ and capillary blood volumes as a percentage of body weight.
--
Michael C. Kohn
Laboratory of Computational Biology and Risk Analysis
National Institute of Environmental Health Sciences
P.O. Box 12233, Mail Drop A3-06
Research Triangle Park, NC 27709-2233
Telephone:
919-541-4929 (voice)
919-541-1479 (fax)
e-mail:
kohn.at.valiant.niehs.nih.gov
WWW home page:
http://valiant.niehs.nih.gov
---
From: "Bonate, Peter, HMR/US"
To: "'PharmPK.aaa.pharm.cpb.uokhsc.edu'"
Subject: RE: PharmPK Rat Organ Weights
Date: Fri, 20 Mar 1998 07:52:44 -0600
Mime-Version: 1.0
A good place to start is:
Davies and Morris: Physiological Parameters in Lab Animals and humans.
Pharm Res 10, 1093-1095, 1993.
Just about any paper on phyisologically-based pk modeling has a table on
weights and flows used. These vary from paper to paper but are usually
close enough.
Do you really expect drug distribution into bone? I would think that
would be pretty unusual and a big flag for most new chemical entities.
Make sure you look at the papers by:
Chen and Gross: Estimation of tissue to plasma partition
coefficients... J Pharmacokin Biopharm 7, 117-125, 1979.
Khor and Mayersohn: Potential errors in the measurement of tissue to
blood distribution... Parts I and II. Drug Metabolism and Disp 19,
478-490, 1991.
Peter L. Bonate, Ph.D.
Hoechst Marion Roussel
Clinical Pharmacokinetics
P.O. Box 9627 (F4-M3112)
Kansas City, MO 64134
fax: 816-966-6999
phone: 816-966-3723
---
From: HBarton.aaa.icfkaiser.com (Barton, Hugh NC01)
To: PharmPK.aaa.pharm.cpb.uokhsc.edu (PharmPK)
Mime-Version: 1.0
Organization: ICF Kaiser International, Inc.
Date: Fri, 20 Mar 1998 09:20:17 -0500
Subject: RE: PharmPK Rat Organ Weights
This reference has much information on absolute and relative tissue
weights, blood flows, ventillation rates etc for rats, mice, and humans.
Brown RP, et al. **********[See Related Articles]
Physiological parameter values for physiologically based pharmacokinetic
models.
Toxicol Ind Health. 1997 Jul; 13(4): 407-484
---
Date: Fri, 20 Mar 1998 09:48:19 -0500
From: Janusz Byczkowski
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Rat Organ Weights
Mime-Version: 1.0
You wrote:
>>> "Richard Knapp"
"...1. Does anyone know of a source for estimates of total muscle,
skeleton,
fat and skin mass relative to body weight for the rat?..."
ANSWER:
Obviously, exact numbers depend on the strain, sex and the age of
rats.
The most complete source of data (known in the near Universe) is
published in a report:
Physiological Parameter Values for PBPK Models (R. Brown, Ed.). A
Report Prepared by the International Life Science Institute, Risk
Science Institute for US EPA in 1994, Washington, DC.
General estimates for the "hypothetical average representative rat"
in this report were derived from experimental mean values reported in
the literature:
From Table 2-5. Relative Organ weight (% Body Weight) in Rats
__________________________________________________________
Organ Mean+_SD n of
studies
________ ___________ ____________
Adipose Tissue - vary greatly, a very crude estimate (10%, or so)
Adrenals 0.019 +_0.007 7
Bone - vary greatly, a very crude estimate (7%, or so)
Brain 0.57 +_0.14
9
GI Tract
Stomach 0.46 +_0.06 4
Small Intestine 1.4 +_0.39 4
Large Intestine 0.84 +_0.04 4
Heart 0.33 +_0.04
9
Kidneys 0.73 +_0.11
12
Liver 3.66 +_0.65
15
Lungs 0.5 +_0.09
7
Muscle 40.43 +_7.17
2
Pancreas 0.32 +_0.07 3
Skin 19.03 +_2.62
5
Spleen 0.2 +_0.05
8
Thyroid 0.005+_0.002 3
___________________________________________________________
If you add these numbers you may account for about 85.5% of the total
body weight, so there is more than that (blood, claws, fur, stomach
and the intestine content, etc).
I hope, this will give you some idea.
My advise: use these as generic estimates - if you need anything more
exact, run your own control for your particular group of rats (When
you have some data, let me know so I could add them to my own database
:-)
Good luck,
Janusz Z. Byczkowski, Ph.D., D.Sc.
ManTech Environmental Technology, Inc.
Wright Patterson AFB, OH
Phone: 937-255-5150 X 3121
---
Date: Fri, 20 Mar 1998 15:55:37 +0100 (MET)
X-Sender: kaltenba.at.centre02.univ-reims.fr
Mime-Version: 1.0
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
From: Matthieu Kaltenbach
Subject: Re: PharmPK Rat Organ Weights
Concerning estimates of total muscle, skeleton, fat and skin mass relative
to body weight for the rat, you may want to check the paper entitled:
Delp MD et al. Distribution of cardiac output during diurnal changes of
activity in rats. Am J. Physiol. 261 (1991) H1487-H1493.
This paper contains extensive listings of rat organ weights.
Matthieu L. Kaltenbach
-------------------------
Matthieu L. Kaltenbach, PharmD, PhD ( )
Laboratoire de Pharmacocinetique ________//_
UFR de Pharmacie \\\\\ /////
Universite de Reims Champagne Ardenne \-------/
51 rue Cognacq-Jay \_____/
F-51100 Reims, FRANCE (_____)
Tel: (33) 03 2689-8077
Fax: (33) 03 2605-3552
E-mail: matthieu.kaltenbach.aaa.univ-reims.fr
---
Date: Fri, 20 Mar 1998 08:10:56 -0800 (PST)
Mime-Version: 1.0
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
From: Jay Tibbitts
Subject: Re: PharmPK Rat Organ Weights
Dr. Knapp:
I have used the CRC Handbook of Laboratory Animal Science (Ed. Edward C.
Melby, N. H. Altman), CRC PRess, Cleveland, OH 1976. Volume III hs an
extensive list of organ weights for various species and strains.
Jay Tibbitts
UCSF Biopharmaceutical Sciences
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Dear Dr. Knapp
It appears that you are going to sample at one time point only to determine
the distribution of your drug and metabolite. In itself that is a risky
proposition as the distribution characteristics will change as a function of
time. If on the other hand you are attempting to determine (qualitatively)
target organs that may get exposed, then perhaps a single time point may be
sufficient. In the latter case it may be advisable to select a time point
where Cmax is achieved rather than base it on a half-life estimate (I
presume you know the elimination and/or the absorption half-life). If you
are able to add more animals to your study you may want to take some
additional time points at one half-life intervals. There are many design
scenarios that can be presented and I may be able to help you with these if
you so wish.
In answer to your question # 1, I have typically used.
1) Caster W.O., Poncelot J., Simon A.B. and Armstrong W.D.; Proc. Soc.
Exp. Bio. Med., 91, 122, 1956
2) Davies B. and Morris T.; Pharm. Res. 10, 1093, 1993.
In answer to your question # 2:
Yes, I have designed and conducted many biodistribution studies in all
animal species and can help you with possible pitfalls and advantages and
limitations of each type of study design.
Anup Zutshi Ph.D.
Battelle
Tel: (614) 424-5997
E-Mail: zutshi.-a-.battelle.org
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