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Dear members,
Just interested to study the possible impact of
several interventions on the occupancy of
post-synaptic alpha 1-a adrenoceptors of the isolated
rat vas-deferens preparations, using phenylepherine as
the agonist and prazocin as antagonist. Currently,
don't plan to use radioligands, do you think I can use
the Schild plot model, to estimate the occupancy, by
computing the y intercept?
Well, if this is accepted, does it give me the right
talking about for example receptor downregulation, if
any?
Thank you
=====
Ahmed M. Abdel-tawab; MD; PhD
Associate Professor,
Department of Pharmacology,
Faculty of Medicine, Ain Shams University,
Cairo, Egypt
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[Two replies - db]
Date: Thu, 11 May 2000 09:36:10 +1200
From: Nick Holford
X-Accept-Language: en
To: PharmPK.-at-.boomer.org
Subject: Re: PharmPK Schild Plot and Occupancy?
The method proposed by Arunlakshana & Schild is based on a pre-computer
era method and uses more or less subjective estimates of the
concentration ratio in the presence of antagonist. It may be better to
describe your data using non-linear regression with a model such as:
E=Emax*C/(C+EC50*(1+A/KI))
where C is agonist conc, A is antagonist conc, Emax and EC50 describe
the agonist properties and KI reflects the antagonist potency.
Note that you cannot estimate agonist occupancy at the receptor binding
site unless you measure its binding directly.
> Well, if this is accepted, does it give me the right
> talking about for example receptor downregulation, if
> any?
You can characterise functional changes in receptor regulation by
changes in Emax or EC50 following interventions that might change
receptor number or sensitivity. Howeveve, in the absence of binding data
you cannot conclude anything about the absolute number of binding sites
or agonist affinity for the binding site.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
---
Reply-To: "W. Webster"
From: "W. Webster"
To:
Subject: Re: PharmPK Schild Plot and Occupancy?
Date: Wed, 10 May 2000 21:21:38 -0400
X-Priority: 3
Try a Rosenthal Plot
WW
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Just one comment in agreement with Nick Holford's remark :
>The method proposed by Arunlakshana & Schild is based on a pre-computer
>era method and uses more or less subjective estimates of the
>concentration ratio in the presence of antagonist. It may be better to
>describe your data using non-linear regression...
>
The attempts to linearize non-linear problems (Schild,
Lineweaver-Burk, etc.) definitely deserve to be sent to the museum.
This is well illustrated in the article by Martin L. Lobemeier,
"Linearization Plots: Time for Progress in Regression", in the issue
73 of the e-journal BioMedNet
(http://www.biomednet.com/hmsbeagle/73/viewpts/op_ed)
Thierry BUCLIN, MD
Division of Clinical Pharmacology
University Hospital CHUV - Beaumont 633
CH 1011 Lausanne - SWITZERLAND
Tel: +41 21 314 42 61 - Fax: +41 21 314 42 66
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