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Dear all,
I'd like to pick your brains with respect to using in vitro microsomal
incubations and free fractions to predict in vivo PK using the well
stirred model.
I've seen 3 versions of the well stirred model: without any free
fraction considerations (earliest), considering blood free fraction
and considering both blood and microsomal free fractions.
If my animal species in vivo PK total clearance predicts great with
one of these three, but poorly with the other two, am I justified to
use the specific equation that works well for my human prediction?
Or has such good prediction in animal species with that one equation
no relevance to the human case?
Thanks for your help,
Dario
[Critique?
http://www.boomer.org/c/p4/ja/Fig1702/Fig1702.html
http://www.boomer.org/c/p4/ja/Fig1704/Fig1704.html
- db]
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I guess its more compound specific. Available old data suggests that
free fraction corrections are more likely to be required when
differences in binding between microsomes and plasma proetins are large.
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The following message was posted to: PharmPK
Dear Dario
I suppose the liver well-stirred model should be always used along
with its
underlying assumptions and if the clearance predictions are poor then we
should identify the real reasons behind such poor predictions rather
than
changing the model assumptions from one drug (species) to another. You
may
find the following article useful.
Yang J, Jamei M, Yeo KR, Rostami-Hodjegan A and Tucker GT (2007)
Misuse of
the well-stirred model of hepatic drug clearance. Drug Metab Dispos
35:501-502.
Regards
Masoud
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