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Dear Colleagues,
We are currently trying to develop a compound where the half-life is
essential. We aim at a half-life in humans of a few minutes. There is number
of drug candidates available, but how do we get a best shoot at selecting
the compound that fulfills this criteria?
Best regards,
Morten Priskorn
Pharmacokinetics
NeuroSearch A/S
Tel: +45 44 60 82 84
e-mail: mp.-a-.neurosearch.dk
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[Two replies - db]
Date: Mon, 27 Sep 1999 11:24:48 +0200
From: Johan Wallin
X-Accept-Language: en
To: PharmPK.aaa.boomer.org
Subject: Re: PharmPK Predictions of half-life in humans
Dear Morten,
If you would like to screen among multiple drug candidates which one has a
suitable half-life there are a few in vitro-methods to use in order to estimate
the half-life. Note that these will only estimate metabolism and not excretion.
The simplest in-vitro method would be incubation with microsomal fraction from
hepatic cells, where the use of incubation with hepatic cells would be a bit
more difficult and expensive, but strenghten the certainty in
prediction at some
level. A third method is incubation with liver slices, which I do not belive is
often done with human samples. These metods will help in exluding unsuitable
candidates, when moving on to in-vivo phase. if the group of
candidate drugs are
unlikely to be excreted via the kidney the predictions will of course be more
exact. Microsomal incubation is not a difficult metod to set up, but to save
time it can probably be done by a consultant laboratory.
Best regards,
Johan Wallin
---
Sender: acy62.-a-.pop.dial.pipex.com
Subject: Re: PharmPK Predictions of half-life in humans
Date: Mon, 27 Sep 99 09:19:04 +0100
x-sender: acy62.at.pop.dial.pipex.com
From: Andrew Sutton
To: "David Bourne", "Morten Priskorn"
Reply to Morten Priskorn:
Dear Morten:
Much depends on the pharmacological activity of the new compound and the
mechanism of its inactivation. If you go back far enough there may be
some clues to duration of action or elimination Pk by comparison with
compounds already known. For example, in the 1970's while searching for
ever quicker neuromuscular blockers to replace suxemethonium, the Allen
& Hanbury's team including David Jack himself, had an IV dose of a
compound that was neutralised by the buffering capacity of blood.. It was
short acting all right, but so painful on injection that the compound had
to be abandoned there and then (without an extensive preclinical
programme of development, incidentally). At Glaxo in the "70s we were
looking for short acting IV anaesthetics and found some amongst the
(progesterone like) steroids and there are publications on their
structure-activity-duration relationships if you know where to look. You
will, I'm sure, find the same for Zeneca's Propafenone in the 80's and
the German compound Propanidid back in the 70's.
Why else would you need such a short acting drug ?
Kind regards
Andrew Sutton
Andrew Sutton MD FFA
ASutton.at.gcpl.co.uk
Guildford Clinical Pharmacology
Innovators in Phase 1 model design
and leaders in Phase 2 recruiting.
Telephone +44 (0) 1483 406886
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[Two replies - db]
Date: Mon, 27 Sep 1999 23:54:53 -0400
From: "Edward F. O'Connor"
Reply-To: efoconnor.-at-.snet.net
Organization: conn chem
X-Accept-Language: en
To: PharmPK.-at-.boomer.org
Subject:
Is the half-life to be in plasma or in the target tissue? Theoretically, an
active ester with an inactive and water soluble metabolite would work Thus the
solubility and possession of an ester bond might be features to select.
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X-Lotus-FromDomain: WOCKHARDT
From: "Yati Chugh"
To: PharmPK.-a-.boomer.org
Date: Tue, 28 Sep 1999 13:05:47 +0530
X-MDaemon-Deliver-To: PharmPK.-at-.boomer.org
Can we really predict with reasonable certainty about the terminal
elimination half life in humans from the in - vivo PK (Serum)data in
mice/rats and how ???
Any comments.
Yati
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)