The genetic variation that exists between breeds of dogs results in a risk of breed-related differences in the effectiveness and toxicological responses to drugs. This potential source of population variability needs to be considered in the design and interpretation of studies of the canine physiology and drug pharmacology.
A list of identified breed-specific idiosyncrasies that can influence drug absorption and metabolism are provided in Tables and (40
). Table includes recognized metabolic idiosyncrasies and Table includes physiologic idiosyncrasies. Abbreviations are provided at the end of each table.
Examples of Breed Related Metabolic Differences
Examples of Breed Related Physiologic Differences
Breed-related differences can influence drug pharmacokinetics and pharmacodynamics. Therefore, there can be discordance in the dose-response relationship across breeds. For example, differences, such as the lower percent body fat seen in the Greyhound, can lead to a lower than expected volume of distribution for lipophilic compounds (43
). This lower percent body fat can result in higher serum drug concentrations as compared to that seen in breeds with a higher percent body fat. Accordingly, Greyhounds are associated with a greater risk of toxicity for lipophilic compounds.
Large breed dogs also tend to be predisposed to sulfonamide polyarthropathy. Reports of sulfonamide arthropathy have been reported in Labrador retrievers, Golden retrievers, Great Danes, Dalmations, Giant Schnauzers, Briards, Weimaraners, Irish setters, Flat coated retrievers, Gordon setters, Springer spaniels, German short haired pointers, and Airedales, with only two cases reported in smaller dogs (one Cocker spaniel and one Pekingese) (55
). This tendency tends to be particular prevalent among Doberman Pinschers, where protein-losing nephropathy, leukopenia, and modest thrombocytopenia have also been observed (55
). The basis for the Doberman’s predisposition to sulfonamide toxicity may reflect the limited capacity of this breed to detoxify the hydroxylamine metabolites of the sulfonamides (56
In another example, the size of a dog appears to influence growth rate, vitamin D3 metabolism and circulating levels of IGF-1 (which indirectly reflects the levels of growth hormone) (57
). Great Danes (GD) have a statistically significantly greater rate of growth as compared to Miniature Poodles, (MP) significantly greater plasma concentrations of growth hormone (approximately 20 versus
7 µg/l for the GD and MP, respectively at 7 weeks of age) and IGF-1 (approximately 400 versus
150 µg/l for the GD versus
MP, respectively at 16 weeks of age), and a significantly lower clearance of vitamin D3 (approximately 0.625 l/kg per day versus
0.3 l/kg per day for the GD and MP, respectively at 19 weeks of age). GD’s also have a significantly higher rate of renal reabsorption of inorganic phosphate as compared to the MP and a significantly greater rate of bone turnover and resorption. Furthermore, the GD has a significantly higher frequency of growth plate irregularities, which may be due to higher levels of calcitonin and/or lower concentrations of vitamin D3 metabolites (relative to the MP). It is also noteworthy that in adult dogs, plasma IGF-1 concentrations are reported to be related to body size (58
) but that intestinal calcium absorption does not appear to be correlated with body size (although it does appear to be correlated with dog age) (60
Considering the potential impact of breed on drug pharmacokinetics and pharmacodynamics, studies employing similar protocols but different breeds can lead to inconsistent results. This can have important consequences in studies where new medications are being evaluated for use in dogs, when determining appropriate medications or dosages in veterinary practice, or when using the dog as a preclinical species for human drug development. For example:
- Platelet aggregation response to arachidonic acid (in vitro assay) was highly dependent upon breed, with some breeds having only a small proportion of individuals exhibiting an irreversible response (e.g., Greyhounds and Beagles) while other breeds (Scottish Terrier) were associated with the majority of individuals having an irreversible response (61). Therefore, breed differences in platelet aggregation responses to certain drugs may be an important consideration when using the dog as a model for platelet-related cardiovascular disorders.
- The Welsh Corgi is known to have an autosomal recessive severe combined immunodeficiency. Male Weimaraners are predisposed to a neutrophil function defect with a primary or secondary reduction in circulating IgG (62). Affected animals of both of these breeds are predisposed to recurrent infections and would likely reveal reduced effectiveness of antimicrobial drugs, especially drugs that work within white blood cells.
- The risk of ibuprofen-related GI ulceration is low for Labrador Retrievers but is very high for German Shepherds (63).
- Several surveys have been conducted to ascertain the occurrence of spontaneous tumors in various canine breeds (64–66). In addition, several sources provide an overview of relative risk of developing malignancies as a function of breed (21,67,68). Despite the absence of detailed epidemiological data, there is a wealth of circumstantial evidence supporting a relationship between breed and the relative risk of certain cancers.
- The Boxer has a significantly greater risk of developing malignant melanoma as compared to other breeds. In contrast, the Chihuahua rarely presents with malignant melanoma (64). Melanoma is most common in older dogs with dark pigmented skin and accounts for between 5% and 7% of all canine skin tumors (69).
- In terms of the risk of developing mammary cancers, it is sevenfold higher in intact as compared to neutered females, and the pure-bred mammary cancer rate is higher in each age group as compared to cross-bred females (p<0.025) (65).
- Osteosarcoma is the most common type of primary bone cancer accounting for up to 85% of tumors that originate in the skeletal system. Of total canine malignancies, osteosarcoma accounts for about 5%. The giant breeds (for example, Great Danes, Mastiffs, Bernese Mountain Dogs, and Irish Wolfhounds) are particularly susceptible. Large breeds such as Rottweilers, Labradors, Golden Retrievers, Shepherds, Dobermans, Weimaraners, Greyhounds and Boxers are also at an increased risk (70,71).
- The use of dogs in studies to assess the human carcinogenicity potential for contraceptive steroids and other compounds may be problematic because certain breeds tend to naturally be more prone to malignant neoplasia (72). Furthermore, while Beagles are concluded to be an adequate model for testing drug carcinogenicity, particularly for contraceptive steroids, certain strains of Beagle may present a higher risk than others (72,73).
Differences across breeds also exist in the dose-response relationship to anticholinergic and prokinetic compounds. Two anticholinergic drugs (atropine and glycopyrrolate) and two prokinetic drugs (metoclopramide and cisapride) were evaluated in four Beagles and four Labrador Retrievers (74
). In Beagles, low doses of atropine [0.02 mg/kg via intramuscular (IM) injection] and glycopyrrolate (0.005 mg/kg by IM injection) completely inhibited gastric motility for at least 30 min, while higher doses (0.04 and 0.01 mg/kg for atropine and glycopyrrolate, respectively) resulted in a cessation of activity for more than 3 h. In Labradors, the effects of glycopyrrolate lasted at least 6-h, regardless of dose, and the effects of atropine lasted for approximately 3-h, regardless of dose. With respect to the prokinetic agents, the increase in amplitude of gastric contractions of Beagles receiving a low dose of metoclopramide (0.3 mg/kg IM) or cisapride (0.2 mg/kg IM) was significant, but higher doses paradoxically caused a lesser increase in the amplitude of gastric contractions. In Labradors, both medications, mainly at higher doses, resulted in an increase in the amplitude of intestinal contraction. However, the low dose of cisapride had no effect, and a low dose of metoclopramide exerted only a transient effect. Cisapride did not affect the frequency of antral contractions in either Beagles or Labradors. In Beagles, metoclopramide resulted in a dose-related increase in the frequency of contraction. Metoclopramide did not increase the frequency of contraction in Labradors.