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Dear All,
Is the hepatic first pass metabolism constant across the animal
species. i.e if we see that a compound is getting first pass
metabolised in rabbits, Can we say with confidence that it would
happen in rats also ???
Any comments would be welcome.
Thanks :
Mubben Khan
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[A few replies - db]
From: horst.beier.aaa.grunenthal.com
To: PharmPK.-a-.boomer.org
Subject: AW: PharmPK First pass metabolism - cross species
Date: Fri, 10 Mar 2000 08:20:00 +0100
My answer is yes and no. In most cases we find first pass metabolism in all
animals investigated in our facilities for a certain compound. But the
amount of drug being metabolised varies widely between the species incl.
humans. As a rule of thumb: The smaller the animal the faster is the first
pass metabolism. More over, the metabolite profile varies between the
species. All this makes it difficult to predict fist pass metabolism is
respect to first administrations in humans. But if we see extensive first
pass metabolism in one species for most compounds there will be significant
first pass metabolism in other species.
Horst
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From: Thomas.Senderovitz.-a-.ferring.com
To: PharmPK.aaa.boomer.org
Subject: RE: PharmPK First pass metabolism - cross species
Date: Fri, 10 Mar 2000 15:19:25 +0100
Dear Mubben,
No - hepatic first pass metabolism can of course change from species
to species.
It is dependant on enzymatic activity - which is of course dependant
of relative amount of each isozyme available etc. For each new drug
this would have to bee proven, e.g. in vitro liver microsoms studies
comparing different species. Note that in vitro data can not always
predict in vivo situations. An example could be production of a
metabolite that inhibits further metabolism of the parent compound in
vitro. In vivo, such a metabolite could be removed, and the
difference between the species would not be as great in vivo as
predicted in vitro. On the other hand, small differences observed in
vitro could be greater in vivo.
In principal, the expected relevant species should be investigated in
vitro (microsomes) before choosing the 2-3 species for further (in
vivo) testing. Human hepatic first pass metabolism (don't forget the
gut!) cannot be completely predicted from animal testing, but some
valuable knowledge can be obtained.
Another factor is of course the degree of solubility of the compound.
The more water soluble, the less prone to hepatic metabolism (and
hence first pass metabolism).
Hope this helps.
Regards,
Thomas Senderovitz
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X-Sender: whittem.at.staff.uiuc.edu
Date: Fri, 10 Mar 2000 09:23:53 -0600
To: PharmPK.-at-.boomer.org
From: Dr Ted Whittem
Subject: Re: PharmPK First pass metabolism - cross species
Mubben,
It is dangerous to assume hepatic metabolism to be constant across
species. The reasons are at least three.
1) Phase I metabolism isoenzymes differ markedly, resulting in major
differences in hepatic clearance - best examples are the NSAIDs.
2) Phase II capabilities differ markedly, e.g. cats are very slow
glucuronidators, dogs cannot acetylate, pigs cannot sulfate, etc...
3) Protein binding and resultant free fraction differs between
species, e.g. ceftriaxone highly protein bound in humans, but < 20 %
in dogs.
That said, allometric scaling of kinetic parameters tends to be
useful for high hepatic clearance drugs.
Ted Whittem
Dept Veterinary Biociences
University of Illinois.
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From: "Stephan, Thomas"
To: "'PharmPK.-at-.boomer.org'"
Subject: RE: PharmPK First pass metabolism - cross species
Date: Fri, 10 Mar 2000 08:01:03 -0800
Greetings Mubben...
First pass metabolism involves metabolism via the liver and to a large
extent the cytochrome P450 enzyme system. It is well documented that these
enzymes can have significant species variation as well as exhibit quite
similar activities toward certain substrates (i.e. see DRUG METABOLISM
REVIEWS (1991), 23(3&4), 355-373). In my experience, broad generalizations
can be dangerous!! If you desire to evaluate the species differences in
metabolism using a relatively inexpensive method, I would suggest incubating
your compound of interest in the presence of liver microsome and s9
fractions from different species and evaluating the disappearance of the
parent/appearance of any metabolites in the system. Comparing these
profiles from the different species can give you a certain degree of
understanding about the potential metabolism in vivo. Another more
expensive approach would be to use liver slices of various species to
determine such profiles. The liver microsomes and s9 fractions from a
variety of species are available commercially or can be isolated in the
laboratory. I would suggest evaluating the compound in mouse, rat, rabbit,
dog, monkey and human in vitro systems to get a nice comparative profile
(i.e. these are the common species that potential pharmaceuticals see when
advancing through development). Hope this helps!!
Tom Stephan, Ph.D.
ICOS Corporation
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From: "Melethil, Srikumaran K."
To: "'PharmPK.at.boomer.org'"
Subject: RE: PharmPK First pass metabolism - cross species
Date: Fri, 10 Mar 2000 13:26:26 -0600
Our knowledge in this area - species differences in first pass metabolism, is
quite limited. So it is best to make the guess that it is "perhaps not", till
supportive data can be obtained.
Sri Melethil, Ph.D.
Professor of Pharmaceutics and Medicine
University of Missouri-KC
School of Pharmacy
Room 203-B, 5005 Rockhilll Road
Kansas City, MO 64110
816-235-1794 (fax: 816-235-5190)
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