Sensitivity to Certain Drugs

Drug sensitivity has been associated with certain polymorphisms in the ABCB1 gene. Dogs that develop this condition present an alteration in the diffusion of certain drugs in tissues such as the brain, which leads to the accumulation of these drugs, causing toxicity.

Definition

Drug sensitivity has been closely related to mutations in the ABCB1 gene encoding P-glycoprotein. This protein is responsible for the distribution of certain drugs: cyclosporine, tacrolimus, ivermectin, loperamide, milbemycin, selamectin, moxidectin, HIV-1 protease inhibitors, steroid hormones and chemotherapeutic agents (doxorubicin). P-glycoprotein is expressed in the liver, kidneys, intestine, and especially in the blood-brain barrier, from where it protects the central nervous system by preventing the diffusion of specific drugs to the brain. Therefore, mutations affecting this transporter will cause the accumulation of drugs in the brain causing adverse reactions.

Genetic basis

Currently, an incomplete dominant inheritance pattern is postulated for this trait. Dogs that carry two copies of the variant are likely to express the trait, while those with a single copy are also at risk of showing sensitivity to certain drugs, although such expression may be milder or not occur at all. In addition, individuals carrying a single copy have a 50% chance of transmitting the variant to their offspring.

Other relevant information

Treatment of drug sensitivity requires, first of all, knowledge of the sensitivity pattern in order to choose effective alternative drugs. It may be necessary to adjust the dosage, frequency of administration or consider combination therapies to achieve the desired therapeutic effect. Breeds of dogs commonly exhibiting this variant include Australian Shepherd Dog, Border Collie, Collie, German Shepherd, Whippet, Mcnab, Huntaway, Old English Shepherd Dog, Shetland Shepherd Dog, Silken Windhound and White Swiss Shepherd.

Bibliography

Mealey KL, Bentjen SA, Gay JM, et al. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. 2001 Nov;11(8):727-33.