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The following message was posted to: PharmPK
Me and my colleague had a debate on whether blood or
plasma clearance should be used for allometric
scaling. I'm hoping to solicit some feedback from
this group.
The argument supporting using blood clearance for
allometric scaling is that the fundamentals of
allometry is based on certain scalable physiological
parameters across species such as cardiac output and
hepatic blood flow. Therefore the most appropriate PK
parameter to be used in allometric scaling should
parallel those physiological parameters as closely as
possible. In this case, blood clearance, rather than
plasma clearance, is better associated with hepatic
blood flow. It is the same rationale why hepatic
extraction ratio has to be calculated using blood
clearance.
The argument supporting using plasma clearance for
allometric scaling is that, in circumstances where B/P
ratio is not available, or when we don't have reason
to believe the presence of significant species
difference in B/P, then plasma clearance is good
enough, given that it's more readily available.
My question is, if we do NOT consider practical
limitation such as unavailability of B/P ratio, from a
pure scientific perspective, isn't it more in line
with the fundamentals of allometry to use blood
clearance as the PK parameter of scaling? Moreover,
in practice, does this scentific basis make people
feel strongly about having to use blood clearance for
allometry and therefore would drive the generation of
B/P data?
Thanks.
Lilian
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The following message was posted to: PharmPK
Lilian,
Most work has been conducted with plasma clearance. So, I suppose
you should go with that. It all boils down to the principle of the
blunt ax: it is cuts the tree, its sharp enough! Good luck, Harold.
P.S. Remember, PK allometry has no theoretical foundation, so its all
empiric.
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The following message was posted to: PharmPK
Lillian,
The premise that "the fundamentals of allometry is based on certain
scalable physiological parameters across species such as cardiac
output and hepatic blood flow" is not correct. See West GB, Brown JH,
Enquist BJ. The fourth dimension of life: fractal geometry and
allometric scaling of organisms. Science. 1999;284(5420):1677-9. This
paper describes how allometry applies to many different kinds of
organisms without any assumption about blood flow.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Dear Lilian,
as previously stated, allometry has not strong anatomical and
physiological basics and, even if by some means also neoteny has been
considered a theoretical basis, at this time the approach remains
empirical.
However, in my personal opinion and as shown in many other scientific
experiences mainly for physical phenomena, we don't believe that our
inability to find strong structural and mechanical basis of allometry
means that allometry has undoubtedly not these basis and can never be
modeled by other, and at this time not used, ways and approaches.
About your question of blood vs. plasma approach, I agree with
previous observations: allometry with plasma data has been used more
and more simply because plasma data are commonly the only available
and simply because often it was confirmed as unfailing in scaling up.
Kind regards
Stefano
--
Stefano Porzio
PK/PD Scientist
RBM S.p.A. - Italy - An affiliate of Merck Serono S.A.
Via Ribes 1
10010 - COLLERETTO GIACOSA (TO)
ITALY
E-Mail stefano.porzio.-at-.merckserono.net
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