Pharmacogenetics is the study of how an individual's genetic composition determines his or her response to drugs. In humans, variations in toxic effects and efficacy of drugs among individuals are mainly determined by genetic polymorphisms in drug-metabolizing enzymes, drug receptors, or drug transporters.1 In dogs, polymorphisms in drug-metabolizing enzymes, drug receptors, and drug transporters have been reported,2–4 and these polymorphisms frequently segregate along breed lines. For example, Greyhounds have low activity of a particular cytochrome P450 enzyme, CYP2B11; following administration of propofol in these dogs, plasma concentrations of the drug are sustained and recovery from anesthesia is delayed, compared with findings in mixed-breed dogs.2,3 A polymorphism in the canine dopamine receptor D4 gene has been detected, and its allelic frequency varies among breeds.4 Perhaps the most striking example of pharmacogenetics in dogs involves the drug transporter P-gp. P-glycoprotein, the product of the ABCB1 (formerly MDR1) gene, acts as an important barrier to the distribution of substrate drugs to selected tissues and restricts access of xenobiotics through the blood-brain barrier, the blood-testes barrier, and the placenta; it also has important excretory functions in enterocytes, biliary canalicular cells, and renal tubular epithelial cells.
The ABCB1-1Δ polymorphism in dogs consists of a 4–base pair deletion mutation. This deletion results in a shift of the reading frame that generates several premature stop codons.5 Because protein synthesis is terminated before as much as 10% of the protein product is synthesized, dogs with 2 mutant alleles have a P-gp null phenotype. Such dogs are approximately 100 times as susceptible to ivermectin-induced neurologic toxicosis as ABCB1 wild-type dogs. These dogs also appear to be highly susceptible to the neurologic adverse effects of loperamide6 and other avermectins, including milbemycin, selamectin,7 and moxidectin.8 Heterozygous dogs appear to have an intermediate phenotype with respect to responses to avermectins. In a recent case report9 of a dog with the ABCB1-1Δ mutation, hematologic and gastrointestinal toxic effects developed following administration of recommended and reduced doses of vincristine; however, the dog tolerated full doses of cyclophosphamide.
The ABCB1-1Δ mutation primarily affects herding breeds of dogs. Results of earlier studies10–13 involving small populations of dogs have indicated that approximately 75% of Collies in the United States, France, and Australia have at least 1 mutant allele. Other breeds that have been reported to be affected with the ABCB1-1Δ mutation include Old English Sheepdogs, Australian Shepherds, Shetland Sheepdogs, English Shepherds, Border Collies, Silken Windhounds, McNabs, and Longhaired Whippets.12 The purpose of the study reported here was to evaluate the breed distribution of the ABCB1-1Δ polymorphism in a large number of dogs in North America, including dogs of several herding breeds in which this polymorphism has been detected and other breeds in which this polymorphism has not yet been identified.
Fujita K, Sasaki Y. Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy. Curr Drug Metab 2007;8:554–562.
Court MH, Hay-Kraus BL & Hill DW, et al. Propofol hydroxylation by dog liver microsomes: assay development and dog breed differences. Drug Metab Dispos 1999;27:1293–1299.
Hay Kraus BL, Greenblatt DJ & Venkatakrishnan K, et al. Evidence for propofol hydroxylation by cytochrome P4502B11 in canine liver microsomes: breed and gender differences. Xenobiotica 2000;30:575–588.
Niimi Y, Inoue-Murayama M & Kato K, et al. Breed differences in allele frequency of the dopamine receptor D4 gene in dogs. J Hered 2001;92:433–436.
Mealey KL, Bentjen SA & Gay JM, et al. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 2001;11:727–733.
Sartor LL, Bentjen SA & Trepanier L, et al. Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. J Vet Intern Med 2004;18:117–118.
Tranquilli WJ, Paul AJ, Todd KS. Assessment of toxicosis induced by high-dose administration of milbemycin oxime in Collies. Am J Vet Res 1991;52:1170–1172.
Mealey KL, Northrup NC, Bentjen SA. Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. J Am Vet Med Assoc 2003;223:1434,1453–5.
Mealey KL, Munyard KA, Bentjen SA. Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of herding breed dogs living in Australia. Vet Parasitol 2005;131:193–196.
Mealey KL, Bentjen SA, Waiting DK. Frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample population of Collies from the northwestern United States. Am J Vet Res 2002;63:479–481.
Neff MW, Robertson KR & Wong AK, et al. Breed distribution and history of canine mdr1-1Δ, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci U S A 2004;101:11725–11730.
Hugnet C, Bentjen SA, Mealey KL. Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of collies from France. J Vet Pharmacol Ther 2004;27:227–229.
Henik RA, Kellum HB & Bentjen SA, et al. Digoxin and mexiletine sensitivity in a Collie with the MDR1 mutation. J Vet Intern Med 2006;20:415–417.
Geyer J, Döring B & Godoy JR, et al. Frequency of the nt230 (del4) MDR1 mutation in Collies and related dog breeds in Germany. J Vet Pharmacol Ther 2005;28:545–551.
Mealey KL, Gay JM & Martin LG, et al. Comparison of the hypothalamic–pituitary–adrenal axis in MDR1–1Ä and MDR1 wildtype dogs. J Vet Emerg Crit Care 2007;17:61–66.