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Is anyone aware of compounds that exhibit poor oral absorption in
rodents but good oral absorption in monkeys or examples of improved
oral absorption as one progresses toward higher animal species?
References would be appreciated.
Thank you.
Salvatore DiStasio
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The following message was posted to: PharmPK
Dear Salvatore DiStasio,
really it's a common experience to see different absorption extents
in different species, however in my experience it's not easy to
identify a trend starting from lower to higher animal species.
Classical allometric approach, when operates well, is easily
applicable to the physiologically-based parameters like clearance and
volume of distribution, but unfortunately it's not at all times
applicable to parameters like absorption.
A way to overcome this problem is the scaling up of absorption by
dedicated software applications able to manage chemical-physical
(solubility, LogD, etc.)and biological (permeability, etc.)
properties of the compound in conjunction with anatomical (gut
districts lumen length, dimensions, surface area, etc.) and
physiological (transit time, gut lumen pH, etc.) of the particular
animal species.
Among a lot of papers where you can find the discussion of these
problems I can suggest you two papers about where species differences
are considered:
van De Waterbeemd H, Smith DA, Beaumont K, Walker DK. Property-based
design: optimization of drug absorption and pharmacokinetics. J Med
Chem. 2001 Apr 26;44(9):1313-33.
[An excellent discussion about properties based concepts and
physiological anatomical issues in early drug disposition studies]
He YL, Murby S, Warhurst G, Gifford L, Walker D, Ayrton J, Eastmond
R, Rowland M. Species differences in size discrimination in the
paracellular pathway reflected by oral bioavailability of poly
(ethylene glycol) and D-peptides. J Pharm Sci. 1998 May;87(5):626-33.
[An example where absorption in human is more similar to the
absorption in rat than to the absorption in dog...]
Best regards
Stefano
Dr. Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA - ZAMBON-GROUP
Taverne - Switzerland
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Dear Salvatore,
I have the same findings as you, poor bioavailability in rodents but
good bioavailability in monkeys. It will be interesting to know whether
these findings are "common" or inherent to our drugs.
Regards,
samia
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Dear Salvatore DiStasio,
really it's a common experience to see different absorption extents
in different species, however in my experience it's not easy to
identify a trend starting from lower to higher animal species.
Classical allometric approach, when operates well, is easily
applicable to the physiologically-based parameters like clearance and
volume of distribution, but unfortunately it's not at all times
applicable to parameters like absorption. A way to overcome this
problem is the scaling up of absorption by dedicated software
applications able to manage chemical-physical (solubility, LogD, etc.)
and biological (permeability, etc.) properties of the compound in
conjunction with anatomical (gut districts lumen length, dimensions,
surface area, etc.) and physiological (transit time, gut lumen pH,
etc.) of the particular animal species. Among a lot of papers where
you can find the discussion of these problems I can suggest you two
papers about where species differences are considered:
van De Waterbeemd H, Smith DA, Beaumont K, Walker DK. Property-based
design: optimization of drug absorption and pharmacokinetics. J Med
Chem. 2001 Apr 26;44(9):1313-33. [An excellent discussion about
properties based concepts and physiological anatomical issues in
early drug disposition studies]
He YL, Murby S, Warhurst G, Gifford L, Walker D, Ayrton J, Eastmond
R, Rowland M. Species differences in size discrimination in the
paracellular pathway reflected by oral bioavailability of poly
(ethylene glycol) and D-peptides. J Pharm Sci. 1998 May;87(5):626-33.
[An example where absorption in human is more similar to the
absorption in rat than to the absorption in dog...]
Best regards
Stefano
Dr. Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA - ZAMBON-GROUP
Taverne - Switzerland
Back to the Top
Dear Salvatore DiStasio,
really it's a common experience to see different absorption extents
in different species, however in my experience it's not easy to
identify a trend starting from lower to higher animal species.
Classical allometric approach, when operates well, is easily
applicable to the physiologically-based parameters like clearance and
volume of distribution, but unfortunately it's not at all times
applicable to parameters like absorption. A way to overcome this
problem is the scaling up of absorption by dedicated software
applications able to manage chemical-physical (solubility, LogD, etc.)
and biological (permeability, etc.) properties of the compound in
conjunction with anatomical (gut districts lumen length, dimensions,
surface area, etc.) and physiological (transit time, gut lumen pH,
etc.) of the particular animal species. Among a lot of papers where
you can find the discussion of these problems I can suggest you two
papers about where species differences are considered:
van De Waterbeemd H, Smith DA, Beaumont K, Walker DK. Property-based
design: optimization of drug absorption and pharmacokinetics. J Med
Chem. 2001 Apr 26;44(9):1313-33. [An excellent discussion about
properties based concepts and physiological anatomical issues in
early drug disposition studies]
He YL, Murby S, Warhurst G, Gifford L, Walker D, Ayrton J, Eastmond
R, Rowland M. Species differences in size discrimination in the
paracellular pathway reflected by oral bioavailability of poly
(ethylene glycol) and D-peptides. J Pharm Sci. 1998 May;87(5):626-33.
[An example where absorption in human is more similar to the
absorption in rat than to the absorption in dog...]
Best regards
Stefano
Dr. Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA - ZAMBON-GROUP
Taverne - Switzerland
Back to the Top
Dear Salvatore DiStasio,
really it's a common experience to see different absorption extents
in different species and, in my experience, it's not easy to identify
a trend starting from lower to higher animal species. Classical
allometric approach, when operates well, is easily applicable to the
physiologically-based parameters like clearance and volume of
distribution, but unfortunately it's not at all times applicable to
parameters like absorption. A way to overcome this problem is usually
considered the scaling up of absorption, in particular by dedicated
software applications able to manage chemical-physical (solubility,
LogD, etc.)and biological (permeability, etc.) properties of the
compound in conjunction with anatomical (gut districts lumen length,
dimensions, surface area, etc.) and physiological (transit time, gut
lumen pH, etc.) of the particular animal species. Among a lot of
papers where you can find the discussion of these problems, I can
suggest two papers about where species differences are considered:
van De Waterbeemd H, Smith DA, Beaumont K, Walker DK. Property-based
design: optimization of drug absorption and pharmacokinetics. J Med
Chem. 2001 Apr 26;44(9):1313-33. [An excellent discussion about
properties based concepts and particular emphasis on contribution of
physiological and anatomical issues in early drug disposition studies]
He YL, Murby S, Warhurst G, Gifford L, Walker D, Ayrton J, Eastmond
R, Rowland M. Species differences in size discrimination in the
paracellular pathway reflected by oral bioavailability of poly
(ethylene glycol) and D-peptides. J Pharm Sci. 1998 May;87(5):626-33.
[An example where absorption in human is more similar to the
absorption in rat than to the absorption in dog...]
Best regards
Stefano
Dr. Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA - ZAMBON-GROUP
Taverne - Switzerland
Back to the Top
The following message was posted to: PharmPK
Dear Salvatore DiStasio,
really it's a common experience to see different absorption extents
in different species and, in my experience, it's not easy to identify
a trend starting from lower to higher animal species. Classical
allometric approach, when operates well, is easily applicable to the
physiologically-based parameters like clearance and volume of
distribution, but unfortunately it's not at all times applicable to
parameters like absorption. A way to overcome this problem is usually
considered the scaling up of absorption, in particular by dedicated
software applications able to manage chemical-physical (solubility,
LogD, etc.)and biological (permeability, etc.) properties of the
compound in conjunction with anatomical (gut districts lumen length,
dimensions, surface area, etc.) and physiological (transit time, gut
lumen pH, etc.) of the particular animal species. Among a lot of
papers where you can find the discussion of these problems, I can
suggest two papers about where species differences are considered:
van De Waterbeemd H, Smith DA, Beaumont K, Walker DK. Property-based
design: optimization of drug absorption and pharmacokinetics. J Med
Chem. 2001 Apr 26;44(9):1313-33. [An excellent discussion about
properties based concepts and particular emphasis on contribution of
physiological and anatomical issues in early drug disposition studies]
He YL, Murby S, Warhurst G, Gifford L, Walker D, Ayrton J, Eastmond
R, Rowland M. Species differences in size discrimination in the
paracellular pathway reflected by oral bioavailability of poly
(ethylene glycol) and D-peptides. J Pharm Sci. 1998 May;87(5):626-33.
[An example where absorption in human is more similar to the
absorption in rat than to the absorption in dog...]
Best regards
Stefano
Dr. Stefano Porzio
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA - ZAMBON-GROUP
Taverne - Switzerland
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