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David,
After having received some replies, I realize that my question wasn't
specific enough. Here is the rephrased question:
Are there any examples of drugs for which the plasma concentration-effect
relationship is better defined using plasma concentration of an inactive
metabolite compared to using the plasma concentration of the active parent
drug? Please provide literature references or other substantiating evidence
if possible.
Thank you for your input.
Bertil Wagner, Pharm.D.
Hoffmann-La Roche, Inc.
340 Kingsland Street
Nutley, NJ 07110-1199
tel: (973) 562-5515
fax: (973) 562-5509
e-mail: bertil_k.wagner.aaa.roche.com
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Surely by definition inactive means it has no effect
The UK NEQAS for Antibiotic Assays is provided by:
Department of Microbiology, Southmead Health Services NHS Trust
Bristol BS10 5NB, UK.
Tel INT+UK+117 9595653 Fax INT+UK+117 9593217
http://www.ukneqasaa.win-uk.net
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Bertil:
How about cotinine for nicotine ?
Andrew Sutton
Guildford Clinical Pharmacology
ASutton.-a-.gcpl.co.uk
Andrew Sutton
ASutton.at.gcpl.co.uk
Guildford Clinical Pharmacology
Telephone +44 (0) 1483 406886
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[Two replies - db]
Reply-To:
From: "Jeff Wald"
To:
Subject: RE: PharmPK Metabolite Question
Date: Mon, 30 Nov 1998 15:02:43 -0500
MIME-Version: 1.0
X-Priority: 3 (Normal)
Importance: Normal
Bertil - If you are better describing the effect relationship with the
plasma concentration of an 'inactive' metabolite than by using the plasma
concentrations of the active parent drug I'd bet dollars to doughnuts that
you have some other sort of delay mechanism that is occurring.
There are two basic classes of PD delays. Delays caused by the kinetics of
the drug (ie. it takes a while for the drug to distribute to the site of
action "the Link model", or it takes awhile for the creation of an active
metabolite, etc...) and the other class is the "indirect response". In the
indirect case, the generation of the response (or the kinetics of the
response) is rate limiting, therefore the shape of the curve is determined
more by the physiological system that you are measuring than the profile of
drug concentrations.
These types of delays are distinguished by different characteristics that
you can usually see graphically if you have multiples dose levels in your
study. They can also be distinguished using your knowledge of the
physiological system that you are trying to model.
Regards, Jeff Wald, Ph.D.
Pharsight Corporation
---
Date: Tue, 01 Dec 1998 10:59:04 -0500
From: "Wagner, Bertil K {PDRD~Nutley}"
Subject: RE: PharmPK Re: Metabolite Question
To: "'PharmPK.-at-.pharm.cpb.uokhsc.edu'"
Mime-Version: 1.0
Dear Dr. Sutton,
Thank you for your insightful comments. We have carefully read you replies
and are pursuing literature searches on the compounds indicated. In
reference to your latest e-mail, it seems that cotinine does possess some
behavioral activity although it lacks cardiovascular effects at
"therapeutic" concentrations achieved during smoking. We are investigating
its relationship as a surrogate marker for nicotine on smoking effects. I
am truly appreciative for your efforts and would welcome additional
comments.
Bertil Wagner, Pharm.D, FCCM
Hoffmann-La Roche Inc.
340 Kingsland Street
Nutley, NJ 07110
(973) 562-5515
bertil_k.wagner.-a-.roche.com
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