theABCB1(formerlyMDR1) gene (See also chapter, “Drug Delivery Systems in
Domestic Animal Species” Sect. 4).P-gp is an ATP-dependent efflux drug trans-
porter protein, located primarily in the intestine, liver, kidney and brain where it
limits systemic and brain uptake of drugs and enhances drug excretion (Mealey
et al. 2008 ). Consequently, loss ofP-gp function (genetically or through drug–drug
interactions) can lead to increased drug levels and enhanced brain penetration of
certain drugs. For a number of years, it was recognised that Collies were unusually
susceptible to the CNS depressant side effects of ivermectin (Paul et al. 1987 ). In
one study, the lethal dose of ivermectin in Collies was only 1/10th to 1/20th of the
lethal dose in Beagle dogs (Pulliam et al. 1985 ). However, it was later shown that
there were no significant differences in plasma pharmacokinetics of ivermectin
between sensitive and non-sensitive Collies, suggesting a role for either enhanced
CNS sensitivity or enhanced brain penetration of drug in susceptible animals or
both (Tranquilli et al. 1989 ). Subsequently, it was demonstrated that mice with
genetic ablation ofMdr1a(the mouse homolog ofABCB1) were also exquisitely
sensitive to the CNS toxic effects of ivermectin (Schinkel et al. 1994 ), which
identified canineABCB1as an appropriate candidate gene for ivermectin sensitivity
in Collies. Examination of theABCB1sequences of three ivermectin-sensitive
Collies revealed an identical 4-bp deletion that causes a frame-shift mutation
resultant premature stop codon and produces a truncated, non-functional protein
(Mealey et al. 2001 ). As probablyP-gp is important for the disposition of many
other drugs in addition to ivermectin, it is likely that dogs with theABCB1-del4 will
be susceptible to the adverse effects of a range of other drugs. Indeed, excessive
sedation with loperamide (Sartor et al. 2004 ) and toxicity of vincristine (Mealey
et al. 2003 ) have been observed in dogs withABCB1-del4.
ABCB1-del4 primarily affects herding breed dogs, particularly Collies (Neff
et al. 2004 ; Mealey and Meurs 2008 ). Seventy-five percent of Collies in the United
States, France, and Australia have at least one mutant allele (Hugnet et al. 2004 ;
Neff et al. 2004 ; Mealey et al. 2005 ; Mealey and Meurs 2008 ). As shown in Table 1 ,
other herding breeds with a relatively high prevalence (10% or more carriers)
include Australian Shepherd, German Shepherd, and Shetland Sheepdog, and
there is also a low prevalence in the Border Collie, Bearded Collie, and Australian
Cattle Dog (Mealey et al. 2003 ; Mealey and Meurs 2008 ). Interestingly, certain
non-herding breeds including the Silken Windhound and Long-haired Whippet
have a high prevalence (31–58%) of the mutation, suggesting common ancestry
with the Collie dog, perhaps reflecting a previous breeding strategy to achieve and
maintain a desirable characteristic. Also noted in Table 1 is that mixed-breed dogs
of uncertain ancestry may be carriers (up to 11%), although as the data were
obtained from a clinicalABCB1–del4 genotyping service, it is likely that the
DNA samples were being submitted for testing by owners and veterinarians
because of suspicion that the dogs might have herding-breed ancestry. In addition
to the clinical implications of theABCB1–del4 mutation, because affected dogs are
essentially a naturally occurring large animal (non-rodent)P-gp knockout model,
they have also been used for research into the role ofP-gp in the blood–brain and
blood–cerebrospinal fluid barriers (Mealey et al. 2008 ). Mutant dogs are also being
Comparative and Veterinary Pharmacogenomics 63