Pharmacologic Implications of MDR1 Mutation & Other Causes of P-glycoprotein Deficiency

In the Literature 

Mealey KL, Owens JG, Freeman E. Canine and feline P-glycoprotein deficiency: what we know and where we need to go. J Vet Pharmacol Ther. 2023;46(1):1-16. doi:10.1111/jvp.13102 

The Research … 

The molecular genetic basis of ivermectin sensitivity in canine herding breeds is P-glycoprotein (P-gp) deficiency, which is caused by a genetic variation in the multidrug sensitivity gene (MDR1 gene, also known as ABCB1 gene) known as the MDR1 mutation.¹  

This study reviewed the role of P-gp in drug disposition and its impact on drug selection in dogs and cats. P-gp is a drug transporter expressed on the surface of cells in many tissues and typically limits entry or promotes excretion of P-gp substrates (ie, drugs transported by P-gp). P-gp function can be impaired in both dogs and cats and can result in significant adverse drug reactions.  

P-gp deficiency can be intrinsic or acquired. Intrinsic deficiency can be due to either an inherited MDR1 mutation (eg, deficiency seen in herding breeds) or spontaneous mutation in any dog, as well as in cats. Acquired P-gp dysfunction occurs when a patient is concurrently given 2 P-gp substrates. These patients are generally able to eliminate one drug at a therapeutic dose without adverse effects, but a second P-gp substrate can compete for limited P-gp binding sites, resulting in higher levels of one or both drugs due to decreased rate of elimination. Higher drug levels can result in adverse drug reactions, especially if one or both drugs have a narrow therapeutic index or margin of safety. 

There are species differences in P-gp substrates; therefore, a drug that is a P-gp substrate in one species should not be assumed to be a substrate in another species.² Several resources list known or suspected P-gp substrates.^1-3

… The Takeaways

Key pearls to put into practice: 

• Any dog or cat can have P-gp deficiency. Instead of adhering solely to a white feet, don’t treat approach, dogs with a breed disposition for this mutation should be tested at a young age and the result kept in their medical record. In addition, any dog or cat that will receive a P-gp substrate with potentially significant adverse effects should be tested prior to treatment. An MDR1 mutation test with a turnaround time of ≈1 week is available.³ Genetic testing is not required to safely administer heartworm preventives. 

• Simultaneous administration of 2 P-gp substrates can cause temporary acquired P-gp dysfunction, regardless of the patient’s MDR1 genotype.  

• In patients with intrinsic or acquired P-gp deficiency, P-gp substrates may need to be substituted with drugs that are not P-gp substrates or are P-gp substrates with a high margin of safety. If a P-gp substrate cannot be substituted, the dose should be reduced by 50% in dogs homozygous for the MDR1 mutation or 25% in heterozygous dogs and dogs with acquired P-gp dysfunction. The dose may be gradually increased by 10% increments if indicated and tolerated.