MDR1

Question 1

What does the mutation in the MDR1 gene (ABCB1) result in in affected animals?

Answer 1

(Defective p-glycoprotein drug efflux pump = multidrug resistance drug sensitivity)

Question 2

What inheritance pattern is associated with MDR1?

Answer 2

(Dominant so heterozygotes will be affected but to a lesser degree compared to homozygotes)

Question 3

What does it mean that the MDR1 mutation has a dominant inheritance pattern?

Answer 3

(Homozygotes will definitely be affected, heterozygotes will be affected but to a lesser degree, and animals without the mutations (ABCB1 wildtype) will be unaffected)

Question 4

P-glycoprotein efflux pumps normally pump drugs in/out (choose) of the CNS.

Answer 4

(Out)

Question 5

(T/F) P-glycoprotein is present at other protected sites, not just the CNS.

Answer 5

(T)

Question 6

What is the purpose of p-glycoprotein pumps present in the biliary tract?

Answer 6

(They pump drug into bile to be eliminated → mutation may prevent drugs from being excreted through the biliary route = accumulation and toxicity)

Question 7

(T/F) Only collies and collie type dogs are affected by MDR1 mutations.

Answer 7

(F, lots of other dogs → chinook, whippet, german shepherds, even random mixed breeds)

Question 8

How can you prevent the more profound and/or prolonged CNS depression that is associated with butorphanol and acepromazine use in MDR1 positive dogs?

Answer 8

(Dose reduction)

Question 9

(T/F) It is safe to use ivermectin (+ other macrocyclic lactones) at label doses in MDR1 positive dogs.

Answer 9

(T, do not use large animal formulation or extra label doses for treatment of mange bc = severe, prolonged, CNS depression)

Question 10

(T/F) The ADEs associated with use of high doses of emodepside in MDR1 positive animals (vomiting, dilated pupils, incoordination, muscle tremors, and seizures) are transient and rapidly go away when the drug wears off.

Answer 10

(T)

Question 11

Why should use of loperamide be avoided in MDR1 positive animals?

Answer 11

(Will cause CNS depression → doesn’t usually cross BBB which is why is it available over the counter (even tho it is an opioid) but it can in MDR1 positive animals)

Question 12

(T/F) Although maropitant and ondansetron can cause mild to moderate sedation in MDR1 positive animals, they can still be used and animals should just be monitored.

Answer 12

(T)

Question 13

Ropinirole/apomorphine (choose) causes severe CNS depression and vomiting (aspiration risk) in MDR1 positive animals.

Answer 13

(Apomorphine, should use ropinirole in MDR1 positive animals)

Question 14

Which analgesic will have prolonged clearance in MDR1 positive animals leading to an increased risk for GI toxicity (they get diarrhea)?

Answer 14

(Grapiprant)

Question 15

What ADEs are associated with use of chemotherapeutics in MDR1 positive animals?

Answer 15

(Myelosuppression and GI toxicity, also death with doxorubicin and actinomycin D)

Question 16

Immunosuppressives like cyclosporine affect what cells that have p-glycoprotein efflux pumps on them?

Answer 16

(Lymphocytes → leads to drug accumulation in lymphocytes and cell death = myelosuppression)

Question 17

What is the general recommendation for dose reduction of p-glycoprotein substrate drugs in heterozygous versus homozygous MDR1 positive animals?

Answer 17

(Heterozygous → 25% dose reduction; homozygous → 50% dose reduction)

Question 18

Which of the following drugs are p-glycoprotein inhibitors/substrates versus inducers?

• Rifampin
• Spinosad
• Glucocorticoids
• Ketoconazole
• Cyclosporine
• Phenobarbital

Answer 18

• Rifampin (Inducer)
• Spinosad (Substrate)
• Glucocorticoids (Inducer)
• Ketoconazole (Substrate)
• Cyclosporine (Substrate)
• Phenobarbital (Inducer)

Question 19

How does a dog get acquired MDR1 deficiency?

Answer 19

(A doctor gives them too many MDR1 substrate drugs → not enough p-glycoprotein pumps to clear both drugs → toxicity)

Question 20

What is the issue with doberman pinschers and their mutation at the cytochrome b5 reductase gene?

Answer 20

(It leads to their inability to clear sulfonamides from their system = toxicity)

Question 21

What is the issue with greyhounds/sighthounds in general and their decreased liver expression of CYP450 2B11?

Answer 21

(That enzyme is the enzyme that metabolizes anesthetics and since sighthounds have less of that enzymes = prolonged anesthetic recovery)

Question 22

Which dog breeds are affected with delayed postoperative bleeding which is a significant and occasionally life threatening postoperative bleeding that can start 24-48 hours following surgery?

Answer 22

(Greyhounds and other sighthounds, they have a mutation in a gene that regulates fibrinolysis, there is a test for it and affected dogs can be given aminocaproic acid prophylactically to prevent bleeding)

Question 23

(T/F) Horses can get acquired MDR1 deficiency.

Answer 23

(T, particularly neonates)