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Dear All,
We have found, not infrequently, a dramatic species difference in
apparent absorption (i.e. low or high bioavailability with a low
clearance drug), between the rodent and non-rodent species, usually dog.
In vitro data also supports a low first-pass effect in all species.
The problem is how to interpret the data, what can be done to clarify
the reasons for the difference and, principally, how to extrapolate
the data to man.
Kind regards
Stefano
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Dear Stefano,
In addition to metabolic differences, the anatomical, physiological,
and biochemical differences in the gastrointestinal (G.I.) tract of
the human and common laboratory animals can cause significant
variation in drug absorption from the oral route. It may really be
the first pass effect metabolism you are looking at; but just a
thought. The review article cited below reviews the anatomical,
physiological, and biochemical differences between the G.I. tracts of
humans and commonly used laboratory animals.
Kararli TT.
Comparison of the gastrointestinal anatomy, physiology, and
biochemistry of humans and commonly used laboratory animals.
Biopharm Drug Dispos. 1995 Jul;16(5):351-80.
I hope this helps.
Regards,
Murad Melhem
Cognigen Corporation
Buffalo, NY
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The following message was posted to: PharmPK
Dear Stefano,
Your dilemma makes a stong argument for the using human microdosing
as a routine part of the development
program. You are not alone either, we hear this often from our
clients, ie confusing animal data.
I wonder if the CYP3A4 humanized mice developed by Frank Gonzalez at
NCI would be superior predictors of BA than
other rodents?
Steve Dueker
Vitalea Science
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