metabolism of antipyrine than beagles, resulting in a significantly longer half-life
(greyhound 1.09 h, beagle 0.55 h) (KuKanich et al. 2007 ). Even within one breed,
such as the beagle, different sub-populations exist. This is illustrated by celecoxib,
where approximately 45% of the animals were extensive metabolisers of celecoxib,
while the remaining 55% of the tested population metabolised the drug only slowly
and incompletely (Paulson et al. 1999 ). Whether or not these differences are related
to polymorphisms in CYP2D15 is unknown.
It is for phase II metabolism that the main qualitative interspecies differences have
been reported and explained by genetic factors, namely deficiencies in glucuronida-
tion in felidae and acetylation in canidae. Glucuronidation represents one of the major
phase II reactions in the metabolism of drugs. Among food-producing animals,
rabbits, pigs, and horses show the maximal glucuronidating capacity towards pheno-
lic substrates, while broilers and cattle display a relatively low conjugation rate.
Cats are known to be very sensitive to phenolic compounds as well as some
drugs such as acetaminophen (paracetamol). It was historically observed that this
sensitivity was attributable to a low glucuronidation capacity, since cats are hardly
able to glucuronate simple phenols like phenol itself and simple aromatic acids such
as benzoic acid. However, cats are able to conjugate diphenyl acetic acid. Recently
Court et al. ( 1999 ) carried out a genetic analysis and found that cats (and other
felines) have a very low glucuronidation capacity due to a mutation in the UDPT
(uridine-diphosphate-glucuronosyl transferase) 1A6 gene, resulting in the expres-
sion of a pseudoenzyme i.e. a non-functional protein.
Interspecies variability in acetylation has been known for many years.N-acetyl-
transferases are widely distributed among animal species and are active in meta-
bolising sulfonamides. Two families ofN-acetyl-transferases (NAT) have been
recognised and called NAT1 and NAT2. Rabbits and pigs have high acetylating
capacity, while chickens and horses are poor acetylators. Dogs and other canids fail
to express functional NAT-1 and NAT-2, which are essential for the excretion of
sulfonamides while in cats, only NAT1 is expressed. In man and rabbit, NAT
activity is subjected to genetic polymorphism resulting in “low” and “high” acety-
lator phenotypes. For further discussion, see chapter, “Pharmacogenomics in
Domestic Animal Species” of this text.
10 Kidney Function and Urinary pH
Kidney function is well-conserved across mammalian species with no major ana-
tomical and physiological differences except concentrating ability related to the
development of the renal medulla. Concentrating ability is low in pigs (urine to
plasma concentration ratio of 3:1) and relatively high in cats (urine to plasma
concentration ratio of 10:1) accounting for the fact that the cat is a species prone
to form calcium oxalate urinary calculi. The consequences of urine dilution on
antibiotic efficacy to treat cystitis are unknown. Urinary pH differences are evident
between species. Urine pH is determined mainly by the composition of the diet,
with alkaline urine generally produced in herbivorous species and acidic urinary pH
40 P.-L. Toutain et al.