used to define the role ofP-gp in drug disposition for preclinical drug development
studies in dogs (Kitamura et al. 2008 ).
Shortly following the discovery thatMdr1agene knockout mice were suscepti-
ble to ivermectin toxicity, a sub-population of the CF-1 strain of mice was identified
that was also susceptible because of a lack ofP-gp expression (Umbenhauer et al.
1997 ). Subsequent studies showed that these mice expressed a truncatedMdr1a
mRNA with deletion of a portion corresponding to exon 23 (Jun et al. 2000 ; Pippert
and Umbenhauer 2001 ). Interestingly, genomic DNA sequencing identified a large
DNA insertion at the exon 23 intron–exon junction with high homology to a murine
leukaemia virus. This insertion resulted in aberrant splicing of the mRNA and the
loss of exon 23 during RNA processing.2.3.2 MRP2 in RatsMultidrug resistance-associated protein 2 (MRP2; also called ABCC2) is an ATP-
dependent active transporter of organic anions, such as glutathione, glucuronide,
and sulphate conjugates located in the canalicular membrane of hepatocytes as well
as polarised kidney and intestinal cells (Wright and Dickinson 2004 ). TR ̄ (trans-
port negative) rats are a mutant strain of the Wistar rat that have an autosomal
recessive defect in the biliary excretion of many organic anions resulting fromTable 1Frequency of ABCB1 genotypes (No. of dogs [%]) determined via analysis of DNA in
buccal swab samples collected from 5,368 dogs in North America between May 1, 2004, and
September 30, 2007
Breed No. of dogs
Genotype
ABCB1 wt/wt ABCB1 mut/wt ABCB1 mut/mut
Australian Shepherd 1,421 754 (53) 525 (37) 142 (10)
Border Collie 306 301 (98) 4 (1) 1 (0.003)
Collie 1,424 322 (23) 598 (42) 504 (35)
English Shepherd 28 28 (100) 0 (0) 0 (0)
German Shepherd 166 149 (90) 14 (8) 3 (2)
Herding-breed mixa 312 276 (89) 32 (10) 4 (1)
Longhaired Whippet 24 10 (42) 14 (58) 0 (0)
Miniature Australian Shepherd 285 180 (63) 96 (34) 9 (3)
McNab 1 1 (100) 0 (0) 0 (0)
Mixed breedb 238 212 (89) 19 (8) 7 (3)
Old English Sheepdog 40 39 (97.5) 1 (2.5) 0 (0)
Shetland Sheepdog 448 395 (88) 47 (11) 6 (1)
Silken Windhound 16 11 (69) 5 (31) 0 (0)
Other purebreeds 659 659 (100) 0 (0) 0 (0)
ABCB1 genotyping was performed according to previously published methods. ABCB1 wt/wt¼
Dogs with 2 ABCB1 wild-type alleles. ABCB1 mut/wt¼Dogs with 1 ABCB1 wild-type allele and
1ABCB1-1Dallele. ABCB1 mut/mut¼Dogs with 2 ABCB1-1Dalleles
aHerding breed mix was a dog in which at least 1 parent was known to be a herding breed.
bDogs were not identified specifically as a herding breed mix or a non-herding breed mix; the
proportion of the former in this group is not known
From (Mealey and Meurs 2008 )
64 C.M. Mosher and M.H. Court