deficient Mrp2 expression (Wright and Dickinson 2004 ; Leslie et al. 2007 ). The
genetic basis for the defect involves a single base-pair deletion at amino acid 393
that results in a frameshift and premature stop codon and truncated Mrp2 protein
(Paulusma et al. 1996 ). TR ̄ rats have been used for a number of years as a model of
human Dubin–Johnson syndrome, which is characterised by a conjugated hyper-
bilirubinaemia resulting from decreased ability to excrete conjugated bilirubin from
the hepatocyte into the bile (Paulusma et al. 1997 ). Like the TR ̄ rat, people with
Dubin Johnson syndrome have various genetic defects in the gene encoding human
MRP2 (Paulusma et al. 1997 ; Wada et al. 1998 ). The TR ̄ rat has also been useful in
identifying drugs and substrates other than bilirubin glucuronide that are substrates
of MRP2 including valproic acid, acetaminophen, and gemfibrozil (Xiong et al.
2000 ; Kim et al. 2003 ; Wright and Dickinson 2004 ).
2.4 Other
2.4.1 Albumin in Rats and Dogs
Polymorphism in the binding of drugs to albumin in rats with consequential effects
on pharmacokinetics has recently been described (Ito et al. 2007 ). Specifically, it
was observed that D01-4582, a drug candidate under development, had over 6-fold
higher plasma clearance values in SD compared with the CD strains of the Sprague-
Dawley rat. Studies using isolated hepatocytes from each strain indicated that
hepatocellular drug uptake was markedly different when incubated in the presence
of plasma. Further studies on plasma protein binding using plasma from six
different rat strains identified low-Kd/high affinity rat strains (CD, EHBR and
Lewis) and high-Kd/low affinity rat strains (SD, Wistar and Brown Norway),
which agreed with the classification based on pharmacokinetic phenotype for CD
and SD rats (Ito et al. 2007 ). Sequencing of the rat albumin gene cDNA identified
11 different polymorphisms. Of these, two amino acid substitution mutations
(V238L and T293I) were identified only in the high-Kdstrains and were suggested
to cause decreased binding affinity of D01-4582 to rat albumin with a resulting
higher clearance. Interestingly, the same group recently reported a similar effect of
two linked amino acid polymorphisms in the canine albumin gene (A335S and
G450E) on the pharmacokinetics of D01-4582 in Beagle dogs (Ito et al. 2009 ). The
prevalence of this allele in 47 Beagle dogs from their colony located in Japan was
40%. As yet, it is not clear what other drugs will be affected by this polymorphism,
and whether Beagles in other colonies or other dog breeds carry the allele.
2.4.2 Arylhydrocarbon Receptor in Mice and Rats
The arylhydrocarbon receptor (AhR) mediates the genetic response to polycyclic
aromatic hydrocarbons and dioxins, resulting in enhanced expression of a multitude
Comparative and Veterinary Pharmacogenomics 65