Sensitivity to Certain Drugs

P-glycoprotein facilitates the active transport of drugs such as ivermectin and macrocyclic lactones out of cells. Dysfunction or deficiency of this transport pump increases sensitivity to these drugs, increasing the risk of adverse reactions due to their intracellular accumulation. P-glycoprotein is encoded by the ABCB1 gene, where a deletion associated with increased susceptibility to certain drugs has been identified.

Symptoms

Clinical signs manifest after exposure to drugs that utilize the P-glycoprotein pump, increasing the risk of severe adverse reactions. These may include neurotoxicity (ataxia, tremors, convulsions, muscle weakness), gastrointestinal symptoms (vomiting, diarrhea, anorexia), cardiorespiratory problems (arrhythmias, respiratory distress), as well as hypersalivation and mydriasis. In severe cases, these reactions may progress to coma, blindness and death.

Disease Management

Management of this condition requires adjusting medication to avoid dangerous drugs, as well as monitoring and treating symptoms in case of accidental exposure.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the cat, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected cat must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between cats carrying genetic variants that may cause disease, even if they do not show symptoms, is not recommended.

Technical report

Sensitivity to certain drugs is closely linked to the function of P-glycoprotein (P-gp), which actively transports drugs out of cells, thus limiting their oral absorption, increasing their excretion and preventing their entry into the central nervous system. This expulsion capacity of P-gp is crucial to protect the body from potentially harmful substances. Genetic variations in the ABCB1 gene, such as the c.1930_1931del deletion, compromise this protective function and can lead to drug accumulation, resulting in severe adverse reactions. Drugs that are P-gp substrates include acepromazine, butorphanol, doramectin, erythromycin, emodepside, ivermectin, milbemycin, paclitaxel, rifampicin and vincristine. For example, cats with the c.1930_1931del variant have been shown to develop severe neurological toxicosis following exposure to antiparasitic products containing eprinomectin. It is also important to note that some research indicates that cats with a single copy of this variant may also be more susceptible to adverse reactions when treated with high doses of drugs that are P-gp substrates.

Most affected breeds

Balinese
Domestic Longhair
Domestic Shorthair
Maine Coon
Ragdoll
Russian Blue
Siamese
Turkish Angora

Bibliography

Mealey KL, Burke NS. Identification of a nonsense mutation in feline ABCB1. J Vet Pharmacol Ther. 2015 Oct.