29 mammalian species, including dog, cat, rat, rabbit, horse, cow, sheep, and pig
(seehttp://www.ncbi.nlm.nih.gov/genomes/static/gpstat.html). This list will likely
continue to grow at a more rapid pace given the recent availability of “massively
parallel sequencing” technologies that enable large-scale “shotgun sequencing” of
entire genomes on a single chip-based platform within a relatively short period of
time (hours for small genomes to weeks for mammalian genomes) (Wheeler et al.
2008 ). Finally, sequence variation in many of these newly derived genomes is being
catalogued to generate single nucleotide polymorphism (SNP) maps that span the
entire animal genome. High density SNP chips are now available through various
commercial sources (such as Illumina and Affymetrix) for species including dog,
horse, sheep and pig, thereby providing a powerful tool for the identification of
genes linked to disease and animal production characteristics, as well as those
associated with altered drug response.
In this chapter, we outline the current status of comparative and veterinary
pharmacogenomics, focusing on drug response phenotypes in companion animals,
farm animals and laboratory animal species that have either an established genetic
aetiology or, at least, reasonable circumstantial evidence for a significant contribu-
tion of genetic variation to phenotype. While it is apparent that the majority of
genetic variants identified to date affect drug absorption and disposition (pharma-
cokinetics), it is likely that variants directly altering drug effect (pharmacodynam-
ics) will continue to be discovered, as the molecular mechanisms underlying drug
action continue to be elucidated. In addition to providing the veterinary clinician
with useful information for the practise of therapeutics, it is envisaged that this will
also provide a resource for individuals involved in veterinary and comparative
biomedical research.
2 Drug Disposition
2.1 Oxidative Enzymes
2.1.1 Cytochrome P450 2D15 in Dogs
In humans, cytochrome P450 (CYP) 2D6 is responsible for the metabolism of a
large number of drugs. It is also polymorphic, with about 10% of White people
classified as “poor metabolisers” (PM) while the remaining 90% are considered
“extensive metabolisers” (EM). In dogs, CYP2D15 is presumed to be the ortho-
logous (equivalent) enzyme to human CYP2D6. Like human CYP2D6, canine
CYP2D15 phenotypic variation has been reported. In a landmark study of the
pharmacokinetics of celecoxib in a colony of 242 Beagle laboratory dogs (from
the USA), there was a clear bimodal distribution of drug clearance with 45% having
an EM and 53% having a PM phenotype (2% were uncertain) (Paulson et al. 1999 ).
There was also a similar distribution of each phenotype within each sex. Evaluation
Comparative and Veterinary Pharmacogenomics 51