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The following message was posted to: PharmPK
Ted, or anybody else:
Do you have a reference for the amount of blood that passes through
the liver and brain per second? You had mentioned it previously
regarding the topic of "very highly protein bound drugs." If there is
a literature reference i would very much like a copy to review and
place in my files.
Regards,
Alan
[On
http://www.boomer.org/c/p4/c18/c1803.html
I referenced Rowland, M. and Tozer, T.N, 1995 Clinical
Pharmacokinetics Concepts and Applications, 3rd ed., Williams &
Williams. Media, PA and Shargel, L., Wu-Pong, S. and Yu, A.B.C. 2005
Applied Biopharmaceutics and Pharmacokinetics, 5th ed., McGraw-Hill,
New York, NY, books at the office so can't check right now - db]
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Dear Alan,
A Literature reference for the blood flow in different organs in
animals and humans:
B. Davies and T. Morris (1993). Physiological parameters in laboratory
animals and humans. Pharm. Res. 10:1093-1095.
Regards,
Martin
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The following message was posted to: PharmPK
Alan,
There are many sources of information on flow rates, some in reviews
like Davies and Morris and some more limited, but I would hesitate to
call any definitive. I was referring to transit times rather than flow
rates. Transit times are more difficult to find; possibly of less use
in mathematical models, but I find them useful for thinking about what
happens. The figures I mentioned for brain were remembered from a
lecture by David Begley. Since you ask for sources, (1) there is a
review by Urban Fagerholm, Drug Discovery Today, 12, 23/24, 1076-1082
December 2007 which quotes ~5s for human brain from a reference therein
(with much other useful numbers) and (2) Margareta Hammarlund-Udenaes et
ala, Pharmaceutical Research 24(5), 1014-25, 2007 which reports two
values for transit time in rat brain: 2.8+/-0.8 and 1.41+/-0.07 seconds
with references. Incidentally, getting back to the bound/unbound
controversy, there are some interesting examples in the Pharm Res
review, where transporters play a role.
I have not checked the liver transit time for some time, and it leads me
to introduce a complication. There are many different transit times,
and there have been many studies using the multiple indicator dilution
technique to measure the different rates of progress of water (exchanges
with intracellular water), small molecules (which may or may not
exchange with intracellular compartments), albumin (which experiences
slowed exchange with the space of Disse) and cells (which are restricted
to the sinusoidal space). If you look at the data, you will see that
passage through the liver is not a case of simple "band-broadening" like
the symmetrical peaks that you see in chromatography, but it is
extremely skewed, with a significant proportion taking several times
longer than the mode average to emerge from the liver. It seems that
not all sinusoids are the same length, or rather not all path-lengths
are the same. I believe this is why the dispersion model was developed,
but it presents a difficult engineering problem for PK modelers.
For comparison, transit times through muscle capillaries range from 0.16
to 1.0 seconds as species body weight increases (up to horse!), though I
have not found human yet. There are lots of publications out there!
Perhaps when I retire ... Meanwhile good hunting.
Ted
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The following message was posted to: PharmPK
Ted,
You wrote:
> For comparison, transit times through muscle capillaries range from
0.16
> to 1.0 seconds as species body weight increases (up to horse!),
though I
> have not found human yet.
If this is the case then it makes me wonder about one of the original
speculations when the effect compartment model first appeared. Stanski
et al. (1979) claimed that the longer Teq for d-tubocurarine with
halothane (7.9 mins) compared to nitrous oxide+narcotic (4.7 mins) was
due to reduced muscle perfusion with halothane. They proposed a
theoretical value of 4.6 mins based on muscle blood flow (30 ml/min/kg)
and a muscle:blood partition coefficient for d-tubocurarine of 0.2.
If the transit time is less than 1 second then how can these long
equilibration times be understood?
How long is the nominal tube that the blood makes its transit in 1
second?
Nick
Stanski DR, Ham J, Miller RD, al e. Pharmacokinetics and
pharmacodynamics of d-tubocurarine during nitrous oxide-narcotic and
halothane anesthesia in man. Anesthesiology. 1979;51:235-41.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.at.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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