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How Should I Treat Dogs & Cats with <em>MDR1</em> Mutation?

How Should I Treat Dogs & Cats with MDR1 Mutation?

Katrina Mealey, DVM, PhD, DACVIM, DACVCP, Washington State University

Pharmacology & Medications

|March 2016|Peer Reviewed

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The Problem

  • Dozens of drugs are transported by the MDR1 (ABCB1-1) gene product P-glycoprotein, but relatively few cause serious toxicity in animals with MDR1 gene mutations.1-3
  • Homozygous vs heterozygous
    • In general, toxicity is most severe in homozygous animals, but toxicity can also occur in heterozygous animals.4,5
  • MDR1 gene mutations have been identified in both dogs (ABCB1-1) and cats (ABCB11930_1931del TC).6,7

Homozygous vs Heterozygous

Homozygous = mutant/mutant

  • Affected dogs and cats have 2 copies of the mutated MDR1 gene and always pass 1 copy of the defective gene to offspring.
  • Homozygotes have potentially fatal sensitivity to certain antiparasitic and chemotherapeutic agents.

Heterozygous = mutant/normal

  • Affected dogs and cats have only 1 copy of the mutated MDR1 gene, but there is a 50% chance of passing the defective gene to offspring.
  • Compared with homozygotes, heterozygotes can react to the same agents when administered at higher doses.

Options & Solutions

The drugs detailed here can cause serious, even fatal, adverse drug reactions in animals with MDR1 mutations unless dose reductions are made. In some situations, use of alternative drugs may be the only therapeutic option.4,5,8-10

Analgesic & Preanesthetic Agents

Acepromazine (as Tranquilizer & Preanesthetic)

  • In dogs with MDR1 mutation, acepromazine tends to cause profound and prolonged sedation.11
  • MDR1 mutation
    • Dose reductions should provide the level of tranquilization and/or sedation expected to occur in a normal/normal dog receiving the full dose.
      • Mutant/mutant dog, dose reduction of 30% to 50% (anecdotal)
      • Mutant/normal dog, dose reduction of 25% (anecdotal)

Butorphanol (as Analgesic & Preanesthetic)

  • Butorphanol, an opioid analgesic used most commonly as a cough suppressant or preanesthetic agent, can cause greater and more prolonged sedation in dogs with MDR1 mutation.12
  • MDR1 mutation12
    • Dose reduction should provide the level of tranquilization and/or sedation as that expected to occur in a normal/normal dog receiving the full dose.
    • Mutant/mutant dog, dose reduction of 30% to 50%
    • Mutant/normal dog, dose reduction of 25%

Antibacterial Agents

Doxycycline

  • Doxycycline is transported by the MDR1 gene product (P-glycoprotein). However, the drug has a wide therapeutic window.13
  • MDR1 mutation
    • The author is aware of strong clinical evidence supporting safe treatment of numerous MDR1 mutant/mutant dogs at regular dosages.12

Erythromycin

  • Erythromycin may cause neurologic signs in dogs with MDR1 mutation.12
  • MDR1 mutation12
    • Mutant/mutant collie exhibited signs of neurologic toxicity shortly after receiving erythromycin.
      • After withdrawal of erythromycin, neurologic signs resolved completely.
      • No other potential causes of neurologic toxicity were identified.

Antiparasitic Agents

Emodepside + Praziquantel (Combination Anthelmintic)

  • FDA approved for use in cats only
    • However, in certain countries (but not the United States), the oral formulation also is available for dogs.14
  • MDR1 mutation
    • Use of this anthelmintic combination can result in neurologic toxicity.
      • ABCB11930_1931del TC mutation in cats would be expected to cause neurologic toxicity.
      • In mutant/mutant dogs, neurologic toxicity has been reported.15,16

Use of an emodepsidepraziquantel combination can result in neurologic toxicity in cats withMDR1mutation, as well as in mutant/mutant dogs.15,16

Macrocyclic Lactones

  • If used according to label doses
    • In mutant/mutant & mutant/normal dogs, all US FDA-approved heartworm preventives (ie, ivermectin, milbemycin, moxidectin, selamectin) are considered safe for use.
      • See specific trademark products for label indications.
  • MDR1 mutation
    • Although the label heartworm prevention doses of the following drugs are safe to use in dogs with MDR1 mutation, higher doses can result in adverse neurologic effects in mutant/mutant and mutant/normal dogs (anecdotal).
    • Ivermectin at doses higher than those for heartworm prevention
      • Mutant/mutant dogs: Doses used for treating mange (300-600 g/kg) can cause severe (potentially fatal) neurologic toxicity.6,17
      • Mutant/normal dogs: The author has been able to use ivermectin to treat sarcoptic mange and generalized demodicosis in some mutant/normal dogs, depending on several factors (eg, other drugs or supplements the dog is receiving, ability of owner to monitor for early signs of toxicity).12
    • Milbemycin, moxidectin, selamectin at higher doses and/or more frequent administration
      • In mutant/mutant dogs, higher doses (generally, 10-20 times higher than heartworm prevention dose) or more frequent use (ie, daily rather than monthly) have been documented to cause neurologic toxicity in dogs with MDR1 mutation.8,17

Until more information is available, use of taxanes in animals withMDR1mutation should be carefully considered.

Chemotherapeutic Agents

Doxorubicin, Actinomycin D (Antibiotic Antineoplastic Agents)

  • Compared with normal/normal dogs, dogs with MDR1 mutation (mutant/mutant and mutant/normal)12,18 are at increased risk for neutropenia, thrombocytopenia, and GI adverse effects
  • MDR1 mutation
    • Initial and subsequent doses recommended by author12
      • Mutant/mutant dogs, initial dose reduction of 50%, with subsequent doses increased as tolerated
      • Mutant/normal dogs, initial dose reduction of 25%, with subsequent doses increased as tolerated

Paclitaxel, Docetaxel (Taxanes)

  • There are no approved formulations of these agents for use in dogs or cats with MDR1 mutation.
    • Paclitaxel caused severe myelosuppression in a mutant/normal dog treated with a reduced dose of this agent.12
      • Additional research is being conducted. Until more information is available, use of taxanes in animals with MDR1 mutation should be carefully considered.
  • MDR1 normal/normal dose recommendations
    • One source cites anecdotal (paclitaxel) protocols in presumed MDR1 normal/normal dogs.19

Vinblastine, Vincristine, Vinorelbine (Vinca Alkaloids)

  • Compared with normal/normal dogs receiving these agents, dogs with MDR1 mutation are at increased risk for5,9,18
    • Neutropenia and thrombocytopenia
    • GI and neurologic adverse effects
    • Neurologic toxicity
  • MDR1 mutation
    • Current recommendations (anecdotal)
      • Mutant/mutant dogs, dose reduction of 50%
      • Mutant/normal dogs, dose reduction of 25%
    • Additional research is ongoing.

Gastrointestinal Agents

Loperamide

  • An opioid excluded from the central nervous system (CNS) by P-glycoprotein
  • MDR1 mutation
    • In mutant/mutant dogs, loperamide can achieve high CNS concentrations, resulting in neurologic toxicity (ie, CNS depression).10,20
      • Can be reversed in short-term by opioid antagonists (eg, naloxone)

Ondansetron

Cats with MDR1 mutation are likely to have drug sensitivities similar to those in dogs with the mutation.

  • The author is aware of several homozygous dogs with MDR1 mutation experiencing mild-to-moderate CNS depression after receiving this agent.12
    • Because ondansetron is a known P-glycoprotein substrate alternate, antiemetics may be more appropriate choices, particularly for cancer patients receiving chemotherapeutic agents that are P-glycoprotein substrates (see Chemotherapeutic Agents, above).12
  • MDR1 mutation
    • In mutant/mutant and mutant/normal dogs, competition for P-glycoproteinmediated biliary or renal excretion among P-glycoprotein substrates may delay clearance and consequently increase toxicity.21

Meeting the MDR1 Challenge

Author Insights

  • The hypothalamicpituitaryadrenal axis
    • Is suppressed in mutant/mutant dogs, as compared to wild-type dogs
    • In situations of stress (eg, severe illness, adverse drug reaction), physiologic doses of corticosteroids are indicated.22
  • Concurrent use of drugs (in particular, ketoconazole and spinosad)
    • Can inhibit P-glycoprotein function, causing a phenotype similar to an MDR1 mutation
  • Cats with this mutation
    • Are likely to have drug sensitivities similar to those in dogs with MDR1 mutation
  • Additional information
    • Methods for testing patients for the canine and feline MDR1 mutation can be found at Washington State University Veterinary Clinical Pharmacology Laboratory.

FDA = Food and Drug Administration, CNS = central nervous system, GI = gastrointestinal

References and Author Information

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

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