Back to the Top
A question from a newbie:
Is it possible for a compound that binds covalently tissue proteins to
look like a compound with a short T1/2 beta time?
And if it is so, how one can prove that short T1/2 beta is because of
the covalent binding in tissues and not because of the fast elimination?
Back to the Top
If you have the radiolabeled drug then you could incubate the drug
with model proteins such as albumin. Then separate the free drug from
the protein and protein-bonded drug by size exclusion chromatography.
Solubilization of the protein would allow radioactivity to be assessed
by liquid scintillation counting (see reference below)
1: J Med Chem. 1985 May;28(5):613-20 Smith RV, Velagapudi RB, McLean
AM, Wilcox RE.
Hope this helps;
Angus McLean
Gaithersburg,
MD 20877
* E-mail angusmdmclean.-a-.aol.com
Back to the Top
The following message was posted to: PharmPK
Dmitry,
Dmitry wrote:
>
> A question from a newbie:
> Is it possible for a compound that binds covalently tissue proteins
to
> look like a compound with a short T1/2 beta time?
> And if it is so, how one can prove that short T1/2 beta is because of
> the covalent binding in tissues and not because of the fast
elimination?
If the binding is truly covalent and irreversible then the binding
process is a true elimination clearance mechanism. If this is the sole
mechanism of elimination (unlikely) or in combination with other
mechanisms for elimination (e.g. kidney, liver, etc) is it quite
possible to have a short half-life. Remember that the classification
of half-lives (alpha, beta, etc) is an artefact of your experimental
design (how long and when you sample) and the sensitivity of your
assay. A better PK description of your compounds properties is in
terms of clearances (distribution and elimination) and volumes
(central and peripheral compartment). You can simulate the time course
from these parameters to mimic the 'half-lives' you observe in your
experimental data.
Distinguishing between elimination due to non-binding mechanisms (e.g.
renal excretion or hepatic metabolism) from elimination by binding is
not straightforward. In a simple case you may know that all non-
binding elimination is by renal excretion. In this case you can
measure renal elimination and calculate renal clearance. The binding
elimination clearance is then obtained by subtracting the renal
clearance from the total clearance obtained from analysis of the
plasma conc time course. If you have no independent measure that
distinguishes the binding and non-binding elimination mechanisms then
you will only be able to make an informed guess based on other
information you might have about your compound.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.aaa.auckland.ac.nz
www.health.auckland.ac.nz/pharmacology/staff/nholford
Back to the Top
The following message was posted to: PharmPK
Covalent binding to protein is functional elimination. Radiolabelled
studies will help resolve issues.
Back to the Top
You can also run some gel studies to confirm protein binding along
with radiolabel studies in animals. You can also run QWBA studies. All
3 studies together will confirm the covalent binding.
Neil
[Quantitative whole-body autoradiography (QWBA) - db]
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "T1/2 beta and covalent binding" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)