Canine and feline P‐glycoprotein deficiency: What we know and where we need to go

In 2001 the molecular genetic basis of so‐called “ivermectin sensitivity” in herding breed dogs was determined to be a P‐glycoprotein deficiency caused by a genetic variant of the MDR1 (ABCB1) gene often called “the MDR1 mutation.” We have learned a great deal about P‐glycoprotein's role in drug disposition since that discovery, namely that P‐glycoprotein transports many more drugs than just macrocyclic lactones that P‐glycoprotein mediated drug transport is present in more places than just the blood brain barrier, that some cats have a genetic variant of MDR1 that results in P‐glycoprotein deficiency, that P‐glycoprotein dysfunction can occur as a result of drug–drug interactions in any dog or cat, and that the concept of P‐glycoprotein “inhibitors” versus P‐glycoprotein substrates is somewhat arbitrary and artificial. This paper will review these discoveries and discuss how they impact drug selection and dosing in dogs and cats with genetically mediated P‐glycoprotein deficiency or P‐glycoprotein dysfunction resulting from drug–drug interactions.