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The following message was posted to: PharmPK
I wonder if anyone would care to offer their rationale for using data
from
in vitro metabolism studies, e.g. metabolite stability in human
hepatocytes,
to guide decisions concerning development candidates. How much weight
does
one put on metabolite stability? Should one perform incubations with
hepatocytes (or microsomes) from multiple species early on in the
process?
What battery of paradigms prove most valuable in screening compounds?
Are
there any book chapters or review articles to recommend?
Any discussion would be most welcome...
Bill O'Neil
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Dear Mr O'Neill,
In this interesting debate, I would put forward the 2 following careful
ideas:
- In the field of ADMET screening, absolute reasoning is difficult.
Unless
one has a reference competitor drug to compare with, what kind of ADME
property exactly would exclude a compound from further development ?
There
is a risk to discard compounds which could find their place on the
market,
some big advantages compensating for a few weaknesses. Besides, the
criterion to apply would highly depend on your subject: personally, I've
heard of people developing drugs that should be rapidly metabolised,
while
in most pharmaceutical projects, people try to retain slowly metabolised
drugs...
- In most cases, information about in vitro metabolic stability of the
compound should be handled as a part of the profile, serving for
compound
selection by comparing profiles, and for guiding the development
process by
putting a flag on potential weaknesses of the compound (e.g., strong CYP
inhibition would prompt in-depth in vitro studies, perhaps even early
clinical studies of drug-drug interaction...).
Yours sincerely,
Frederic MASSIERE, PhD
BIOPREDIC
14-18 rue du professeur Jean Pecker
F-35000 Rennes, France
frederic.massiere.at.biopredic.com
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)