used in poultry. One likely reason for their high susceptibility in horses is their
relative inability to demethylate compounds that are not CYP2D substrates. Com-
parative investigations with microsomes from various animal species, including
horses, pigs, broiler chickens, cattle and rats, showed that the horse had the lowest
catalytic ability to demethylate (and hence detoxify) monensin (Nebbia et al. 2001 ).
Comparative metabolism is also relevant when identifying animal models for
humans that have an appropriate similarity, as required for regulatory toxicology.
With the aim of establishing the best animal model for human CYP450-related
research Bogaards et al. ( 2000 ), undertook a comprehensive comparative investi-
gation of the enzyme activities and kinetic parameters of nine prototypical sub-
strates for individual CYP450 activities in liver microsomes derived from mice,
rats, rabbits, dogs (beagle), micropigs (Yucatan), monkeys (Macaca fascicularis)
and man. The overall conclusion of this comparison was that none of the investi-
gated species matched all the typical CYP450 activities as described in humans.
This may also be true within a species when some breeds are selected to fit
laboratory conditions, as in the case of minipigs (Go ̈ttingen minipig and the
Yucatan micropig) that have a higher total CYP450 activity than farm breeds of
pig (Sakuma et al. 2004 ; Vaclavikova et al. 2004 ).
In veterinary medicine, inter-species quantitative differences in phase I and
qualitative differences in Phase II metabolism have been known for several dec-
ades. Examples are the poor capacity of the cat to carry out some glucuronidations,
the deficiency of dogs for acetylation reactions and the low level of sulphate
conjugation in pigs (Baggot 1977 ).
A common assertion in veterinary pharmacology is that in general drugs have
lower clearance in carnivores than in herbivores with omnivores having an inter-
mediary position. Herbivores are also reported to be well-endowed with oxidative
enzyme systems such as those of the cytochrome P450 group, providing rapid drug
clearance for drug elimination by hepatic metabolism. An historical example is
salicylic acid, a ubiquitous plant stress compound, found in high concentrations in
some forage like lucerne. The terminal half-life of salicylic acid varies considerably
between species between less than one hour in herbivores (cattle, horses), from 3 to
6 h in omnivores (man, pigs) and up to 9 h in dogs (Lees 2009 ). In cats the half-life
is even longer (22–48 h) due to a deficit in glucurono-conjugation. Several other
examples may be cited from the literature, illustrating a faster clearance of drugs in
herbivores but more recent functional and genetic studies have shown that there are
no common patterns distinguishing polygastric ruminants from the monogastric
species like pigs, and even amongst ruminants there are no obvious links between
cattle and sheep. However some differences exist, with goats having generally a
more active metabolism than either sheep or cattle. This is linked to their respective
feeding behaviour; goats are natural browsers that can stand on their hind legs or
even climb trees. They preferably eat leaves, shrubs, flowers and fruits, thus
choosing the most nutritious available food but also the portions of plants contain-
ing many toxic alkaloids that need to be metabolised by a hepatic first pass effect.
In contrast, cattle are a non-selective bulk feeder that grazes non-selective grass
generally low in terms of alkaloid content.
38 P.-L. Toutain et al.