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Dear All,
I have recently been reading up on the subject of Allometric scaling of
Xenobiotic clearance and I was wondering whether anyone out there could
help
me. The literature so far seems to contain a wealth of information on
the
use of allometric scaling for "extensively metabolised" drugs but very
little information on scaling when the dominant excretion mechanisms are
either biliary or renal in nature (unchanged drug). Does anyone know
of any
good reference material or examples which deal with either the
prediction to
human or experimental findings when biliary and renal excretion are
dominant
in the animal models tested?
Many thanks in anticipation of your help,
J. Bennett
Dr J. Bennett
Medicinal Chemistry
Organon Laboratories Ltd.
Newhouse
Scotland
United Kingdom
ML1 5SH
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Hi Jonathan,
I don't know that I can shed light on the use of allometry with respect
to
situations where biliary and/or renal excretion are dominant. However,
there
have been some good attempts to address biliary excretion effects on
CLint,all through the examination of hepatic uptake and canalicular
efflux
in hepatic clearance models. Two good examples are:
Yamazaki M et al.,(1996) Recent advances in carrier-mediated hepatic
uptake
and biliary excretion of xenobiotics. Pharm. Res. 13: 497-513
and
Abu-Zahra T and Pang KS., (2000) Effect of zonal transport and
metabolism on
hepatic removal: enalapril hydrolysis in zonal, isolated rat
hepatocytes in
vitro and correlation with perfusion data. Drug Met. Dispos. 28: 807-813
With regards to animal experimental findings, a search of papers
produced
involving the following authors: Yuichi Sugiyama, K. Sandy Pang, Dirk
Meijer
or Peter Meier should provide you with more than enough data regarding
their
investigations of biliary excretion and hepatic uptake and the
transporters
implicated in this.
I hope this helps,
Mark Baker
M. Baker
DMPK and Pharmacology
Celltech R & D Ltd.
Slough
Berkshire
England
SL1 4EN
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J Bennett wrote:
> I have recently been reading up on the subject of Allometric scaling of
> Xenobiotic clearance and I was wondering whether anyone out there could
> help
> me.
If you look beyond the drug xenobiotic literature you will find that
glomerular filtration rate (a form of clearance parameter) you will
find both experimental and theoretical reviews (West et al. 1997,1999,
Singer 2001) of the allometric relationship for renal (GFR) and
non-renal function (metabolic rate). There is strong evidence that
allometric models are excellent descriptors of the relationship between
weight and a broad range of functional and structural properties.
> The literature so far seems to contain a wealth of information on
> the
> use of allometric scaling for "extensively metabolised" drugs but very
> little information on scaling when the dominant excretion mechanisms
> are
> either biliary or renal in nature (unchanged drug). Does anyone know
> of any
> good reference material or examples which deal with either the
> prediction to
> human or experimental findings when biliary and renal excretion are
> dominant
> in the animal models tested?
Experimental evaluation of prediction to humans is fraught with
difficulties because of confounding factors e.g. interspecies
differences in plasma protein binding, temperature (Bonate
2000,Gillooly et al. 2001). However, if all other things are equal
(e.g. protein binding, age, disease, environmental exposure) then I
would expect the clearance of drugs by biliary or renal excretion to be
predictable, in the first instance, with an allometric power
coefficient of 3/4.
I also recommend looking at
http://www.anaesthetist.com/physiol/basics/scaling/Kleiber.htm for an
amusing and illuminating discussion of the pros and cons of various
theories of allometric scaling.
Bonate PL, Howard D. Prospective allometric scaling: does the emperor
have clothes? J Clin Pharmacol 2000;40(4):335-40.
Gillooly JF, Brown JH, West GB, Savage VM, Charnov EL. Effects of Size
and Temperature on Metabolic Rate. Science 2001;293:2248-2251
Singer MA. Of mice and men and elephants: metabolic rate sets
glomerular filtration rate. Am J Kidney Dis 2001;37(1):164-178.
West GB, Brown JH, Enquist BJ. A general model for the origin of
allometric scaling laws in biology. Science 1997;276:122-26.
West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal
geometry and allometric scaling of organisms. Science
1999;284(5420):1677-9.
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Dear Jonathan,
A colleague recently gave me an article concerned with allometric
scaling
of compound demonstrating extensive biliary excretion of an
acyl-glucuronide and subsequent enterohepatic recirculation of the
parent
drug following cleavage of the metabolite in the gut.
Ward, K. W., L. M. Azzarano, et al. (1999). Preclinical
pharmacokinetics and interspecies scaling of a novel vitronectin
receptor antagonist.
Drug Metab Dispos 27(11): 1232-41.
> From what I can remember of the literature, clearance for compounds
> which are exclusviely eliminated via filtration in the kidney should
> scale well
as there is a strong allometric relationship for glomerular filtration
rate across species.
Best Regards
Alex
Dr. A.J.MacDonald
Principal Scientist
Novartis Pharma AG
Modelling and Simulation
ICPP-PCS,WKL135.1.67
CH4002,Basel
Switzerland
(T) +4161 696 77 98
(F) +41 61 696 69 92
email: alex.macdonald.at.pharma.novartis.com
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This message was forwarded to me by a colleaque. I am currently working
on
allometric scaling and came up with a reference
suggestion on the subject:
Mahmood I: Interspecies scaling of renally secreted drugs. Life Sci.
1998;63(26):2365-71
I hope this will be useful.
Best regards
Sanna Salento
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)