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Dear Colleagues,
Does it make sense to fit the concentration-time data
for a compound with relatively low Vd (close to blood
volume) into a 2-compartment model? Can we have a
distribution phase when Vd is relatively low (close to
blood volume)?
Rostam
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[Three replies - db]
From: Jeffrey Larson
Date: Thu, 20 Jun 2002 08:40:26 -0500
To: david.-at-.boomer.org
Subject: RE: PharmPK Re: Volume of Distribution
Hi Rostam
Absolutely it makes sense to use a 2-compartment model if this is what your
data suggests. Monoclonal antibodies given IV are a good example of a class
of molecules which have a Vd approximating plasma volume and have a
relatively quick distribution phase and a long terminal half-life. I'm sure
others will comment on their experience with other relevant compounds.
Cheers!
Jeffrey L. Larson, Ph.D.
Director of Toxicology and Pharmacokinetics
Tanox, Inc.
4888 Loop Central Drive
Houston, TX 77081-2225
(713) 578-4212
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From: "Kavanagh, Ronald E"
Date: Thu, 20 Jun 2002 09:58:05 -0400
To: david.-a-.boomer.org
Subject: RE: PharmPK Re: Volume of Distribution
Yes under certain circumstances as with aminoglycosides.
Ron Kavanagh
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From: "David Foster"
Date: Thu, 20 Jun 2002 07:45:43 -0700
To: david.-a-.boomer.org
Subject: Re: PharmPK Re: Volume of Distribution
Yes, and your data will tell you. If you have good data at the beginning of
the experiment and you can clearly see the data are not monoexponential
(assuming a linear system and a bolus injection - if these assumptions are
not met, the situation will be different), you need more complexity in your
model.
In my experience, one tends to run into trouble when one forces a simple
model on more complex data.
David Foster, PhD CEO
SAAM Institute, Inc
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Another example of of long-circulating, quick distributing compounds would be
many of the polyethylene-associated molecules including proteins as well as
liposomes.
Charles Engbers
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I think your correspondents have misinterpreted Rostam's question.
It is not just that the plasma profile is bi-exponential but that the
volume increass from a small value (approximately plasma volume)
to a value that is not very much larger (if I remember correctly 4-
5L). To blindly apply a two compartment model to this situation is
dangerous as it does not make physiological sense.
I have come across this situation recently and I don't have a
solution. However some possibilities spring to mind
1) Firstly one would have to rule out a data analysis artifact, in that
the second phase had not been sampled sufficiently to properly
define the "second compartment".
2) Saturable protein binding in a true one compartment model gives
the illusion of a bi-exponential disappearance. Basically at higher
concentrations the binding becomes saturated and clearance is
higher than in the unsaturated state. A dose ranging study (and
measurement of the unbound concentration) could sort this out.
Low doses would appear to be monexponential.
3) Chemical degradation in plasma may give rise to sufficiently
complicated kinetics again to give what appears to be bi-
exponential behaviour for essentially a drug which does not get out
of plasma. I don't have an actual example of this but the muscle
relaxant atracurium might fit the bill.
I would be interested in hearing of other possibilities
Leon
Leon Aarons
School of Pharmacy and Pharmaceutical Sciences
University of Manchester
Manchester, M13 9PL, U.K.
email leon.aarons.at.man.ac.uk
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Charles,
Thanks for your comment. Your example was quite
interesting but I am not clear what do you mean by
long-circulating. Are you referring to a long a phase
or a + b phase or this is kind of a new concept
similar to MRT (but in this case Mean Residence Time
of the drug in plasma or blood). I am trying to
understand whether long-circulating and quick
distributing is in conflict; if a compound is
long-circulating how can it be quick distributing?
Unless otherwise we are talking about two different
entities. For example, in case of liposomal drug we
may have a long circulating liposome but the
encapsulated drug may distribute very quickly once is
released. It that why you meant?
Rostam
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If we are in brainstorming mode, I'd add to the conceivable "mechanisms"
- possibility of underestimating Vss by ignoring peripheral
elimination
- modest uptake by specific organs or zones (eg lung)
There are some text-book equilibrium models which if taken too literally
would say that a drug sealed within plasma vasculature can have a
distribution a volume as low as 3l/70kg for plasma (or 4L /70kgwith even
distribution into blood) but that this equilibrium volume would have to jump
to a minimum of ~7.5 L if the interstitial space was involved (taking into
account protein binding). Whilst these are excellent guidelines for learning,
they should surely not cramp our imagination in practice. Equilibrium is an
idealisation for a fiinite time experiment (ie indistinguishable from
ignoring very slow processes) and the idea of a single compartment for
interstitial space likewise. One might imagine for example that the
interstitial fluid in a rapid exchanger like the lung had a different kinetic
relevance to that in the deepest nooks of connective tissue and that drug
diffusion, blood and lymph flows were insufficient to iron out the
differences.
But if your total volume is about 4L per 70kg, and your central volume is
about 3L per 70 kg, blood cells are the first port of call.
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