by the oral route and having a poor bioavailability and also extensively excreted in
the bile (such as oxytetracycline) or by enterocyte efflux (doxycycline) after
parenteral administration should not be used or should be used with caution in
horses and rabbits. Lincomycin and clindamycin in horses and penicillins (amoxi-
cillin, ampicillin) and some cephalosporins (ceftiofur) in rabbits, irrespective of
route of administration are well-recognised to be associated with enterocolitis and
should be avoided in these hindgut fermenters. Trimethoprim-sulfonamides and
macrolides, such as erythromycin and spiramycin, have also been reported to
disrupt horse gut flora. It is interesting to note that this disruption may be more
marked in some parts of the world than others, as is the case for doxycycline. This
drug is considered to be dangerous for horses in Europe but safer in the USA,
possibly a consequence of regional differences in gut flora.
In horses, a large fraction of the oral dose of administered drugs of the NSAID
class, including phenylbutazone, flunixin, and meclofenamic acid may be adsorbed
onto the cellulose and conveyed to the caecum and proximal colon in bound and
non-absorble form, where cellulose digestion takes place releasing the adsorbed
drug. This explains the profound influence of the diet and the schedule of drug
administration in relation to feeding on the bioavailability (rate and extent of
absorption) (Maitho et al. 1986 ; Lees et al. 1988 ). This also is a likely explanation
of the local side-effects of NSAIDs on the digestive tract in horses; erosions may
occur in the distal part (colon) rather than, or as well as, in the stomach as in other
monogastric species.
9 Species Variation in Drug Metabolism
Biotransformation is a major factor accounting for species differences in the
disposition of drug. The group of P450 cytochromes (CYP450) represents a large
superfamily of oxygenases. The CYP450 enzymes are considered to be the most
important metabolising enzymes for xenobiotics. In veterinary medicine, one of the
main motivations to study drug metabolism across different animal species is the
need to identify and describe the depletion of residues in the tissues of farm animals
intended for human consumption (see chapters, “Pharmacogenomics in Domestic
Animal Species” and “Drug Delivery Systems in Domestic Animal Species” of this
text). Hence, knowledge of biotransformation in cattle has been used to predict the
biotransformation (and tissue distribution) in sheep, which is classified in most
countries of Europe as a minor species. It seems that the inter-species differences
are so great that a prediction of biotransformation in sheep from cattle data is not
valid (Watkins et al. 1987 ). The same conclusion was drawn for avian species,
making a cross-species comparison with poultry virtually impossible (Cortright and
Craigmill 2006 ).
Another objective of studies of comparative metabolism is to explain major
interspecies differences in drug effects including safety. In clinical practise, fatal
intoxication may occur in horses exposed to monensin, an ionophoric coccidiostat
Species Differences in Pharmacokinetics and Pharmacodynamics 37