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ABCB1 Deletion Mutation & Drug Reactions in Cats

Clinician's Brief (Capsule)

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P-glycoprotein (P-gp) is the product of the ABCB1 (formerly MDR1) gene. Dogs with the ABCB1-1Δ mutation are at increased risk for serious adverse reactions to P-gp substrate drugs. The goal of this study was to sequence the coding region of the gene in cats that experienced adverse reactions to P-gp substrate drugs (eg, macrocyclic lactones, loperamide, vinca alkaloids). Eight cats that had clinical signs of central nervous system (CNS) toxicosis after receiving ivermectin (n = 2), combination moxidectin and imidacloprid (n = 3), combination praziquantel and emodepside (n = 1), or selamectin (n = 2) at doses not expected to cause adverse reactions were tested. DNA was also collected from 1 cat treated with praziquantel-emodepside that did not develop CNS toxicity. DNA from 105 non-phenotyped cats was also obtained from a DNA bank. 

The most significant finding was a nonsense (deletion) mutation in 1 of the ivermectin-treated cats. This cat was homozygous for the deletion mutation. The other cats were all homozygous for the wild-type allele. The nonsense mutation was identified in 4/105 nonphenotyped cats (1 homozygous and 3 heterozygous). The authors conclude that cats with the described nonsense mutation would be expected to show susceptibility to adverse effects of P-gp substrate drugs, similar to dogs with the ABCB1-1Δ mutation. 

Commentary

Genetic predisposition to macrocyclic lactone sensitivity is widely reported in dogs, and testing is available for the ABCB1 deletion in this species. This study represents the first report of genetic associations with adverse drug reactions to P-gp substrates in cats. Although the most significant ABCB1 mutation had a low prevalence in a phenotypically normal population of cats (4%), clinicians should be aware that clinical signs can occur in these cats even at therapeutic doses of macrocyclic lactones. It is also possible that cats with this mutation could be at higher risk for adverse drug reactions to other P-gp substrate drugs. Currently, genetic testing is not commercially available for cats. Hopefully, future studies will further elucidate the role of genetics in feline macrocyclic lactone sensitivity.—Jennifer Reinhart, DVM, MS, DACVIM (SAIM)

References

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