ASK THE EXPERT

MDR1 GENE MUTATIONS & DRUG THERAPY

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

T he MDR1 (ABCB1) gene encodes P-glycoprotein, a drug transporter that

plays a key role in drug disposi-tion. P-glycoprotein, a critical component of the blood-brain barrier, prevents entry of many potentially toxic compounds into the CNS.1 P-glycoprotein also promotes drug excretion into bile and urine.1

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What do I need to know about the MDR1 gene?

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Defective P-glycoprotein function can lead to severe, potentially fatal, adverse drug reactions because of enhanced CNS exposure to drugs (lack of functional P-glycoprotein at the blood-brain bar-rier)2,3 or enhanced systemic exposure to drugs (lack of P-glycoprotein- mediated biliary and/or renal drug excretion).4,5

What Are the Causes of P-Glycoprotein Dysfunction?Distinct mutations of the MDR1 gene have been described in both dogs2 and cats.6 In dogs, a 4-base pair deletion mutation known as the MDR1 mutation or ABCB1-1∆ creates a stop codon that prematurely terminates P-glycoprotein synthesis.2 Dogs that are homozygous for this mutation have no P-glycoprotein function, whereas heterozygotes have partial P-glycoprotein function. In cats, a 2-base pair MDR1 deletion known as ABCB11930_1931del TC creates a prema-ture stop codon that can lead to an abnor-

mally truncated P-glycoprotein, with similar impairments of P-glycoprotein function as those described in dogs.6

Defective P-glycoprotein function can occur in dogs and cats with MDR1 muta-tions but can also result from drug-drug interactions.4,7 Several commonly used drugs can inhibit P-glycoprotein func-tion, even in animals with normal MDR1 gene structure. Consequently, veterinarians may encounter dogs and cats with intrinsic (genetically mediated) P-glycoprotein dysfunction, as well as with extrinsic, or acquired, P-glycoprotein dysfunction (animals receiving a drug that inhibits P-glycoprotein function).

To avoid causing P-glycoprotein– associated adverse drug reactions, veterinarians should consider all potential causes of P-glycoprotein dysfunction—both intrinsic and acquired.

Which Drugs Should Be Avoided or Used at Reduced Doses?Not all drugs must be avoided in animals with altered P-glycoprotein function; many drugs can be used safely with no need to alter dose. However, animals with altered P-glycoprotein function have been documented to expe-rience enhanced toxicity to the drugs listed in Table 1.

Which Drugs Inhibit P-Glycoprotein?In MDR1 wild-type dogs (and presumably cats), ketoconazole and spinosad are most often associated with severe adverse effects because of their ability to inhibit P-glycoprotein function.4,7,14 Ivermectin toxicosis has been documented in MDR1 wild-type dogs receiving ivermectin in combination with either ketoconazole or

h Homozygous = mutant/mutant: Affected animals have 2 copies of the mutant allele and always pass 1 copy of the defective gene to offspring. Homozygotes are more likely to have severe (life-threatening) adverse drug reactions.

h Heterozygous = mutant/normal: Affected animals have 1 copy of the mutant allele and 1 copy of the normal allele and have a 50% chance of passing the defective gene to offspring. Heterozygotes tend to have less severe adverse drug reactions as compared with homozygotes.

May 2016 cliniciansbrief.com 17

spinosad.15 In addition, severe vinblastine toxicosis was documented in an MDR1 wild-type dog concurrently receiving ketoconazole.7

Which Dog Breeds Are Affected?The MDR1 mutation has been identified primarily in dogs of herding breed ancestry. In fact, all dogs affected by MDR1 are thought to be descendants of a single dog that lived in Great Britain before the genetic isolation of breeds.16 Table 2, next page, lists breeds and approximate frequency of the MDR1 mutation.

Can Mixed Breeds Be Affected? Mixed breeds can be affected because dogs only need to receive 1 copy of the mutant MDR1 allele from a parent with at-risk breed lineage. Thus, a dog with any herding breed in its ancestry may have the MDR1 mutation and be at risk for drug toxicity. The author is aware of many mixed-breed dogs that can harbor the MDR1 mutation despite having no obvious physical characteristics that would suggest herding breed ancestry (Figure 1, page 19). Based on anecdotal clinical findings and observations, many mixed-breed dogs have experienced seri-ous adverse effects because they were treated with P-glycoprotein drugs before being tested for the MDR1 mutation.8

Why Are Clients with Pets Affected by MDR1 Mutation Apprehensive About Using Drugs?Clients with pets affected by the MDR1 mutation may be apprehensive about giving any drug to their pet. This reluc-tance may be caused by accessing false information:

h The information cited on some web-sites is unreliable and inaccurate. For

example, based on in vitro studies of drugs experimentally shown to be transported by P-glycoprotein or on studies conducted in rodents or humans (not in dogs and cats), some websites may falsely cite drugs as being unsafe to use in animals with P-glycoprotein dysfunction.17

TABLE 1

DRUGS TO AVOID OR USE AT REDUCED DOSES2,3,5,7-13

Drug Category Specific Agents

Analgesic/sedative AcepromazineButorphanol

Antibacterial Erythromycin

ANTIPARASITIC

Macrocyclic lactones*

Octadepsipeptide

DoramectinEprinomectinIvermectinMilbemycinMoxidectinSelamectin

Emodepside

CHEMOTHERAPEUTIC

Antibiotic/antineoplastic agents

Vinca alkaloids

Taxanes

Actinomycin DDoxorubicin

VinblastineVincristineVinorelbine

DocetaxelPaclitaxel

GI

AntidiarrhealAntiemetic

LoperamideOndansetron

*At extralabel doses only; label doses for heartworm prevention in dogs and cats are safe.

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h Metronidazole is inappropriately listed by many websites as a drug that should not be used in animals with P-glycoprotein dysfunction.

• Although metronidazole can cause neurologic toxicity, it is not trans-ported by P-glycoprotein.

• Rather, the risk for toxicity increases with increased dose and duration of therapy19 and is not related to P-glycoprotein function.

h In addition, websites may inappropri-ately state that ivermectin should never be used in dogs and cats.

• Ivermectin administered at the man-ufacturer’s label dose can be used in dogs, including herding breeds, with MDR1 mutation.20

• All FDA-approved heartworm preven-tion products licensed in the United States have been tested and found to be safe in dogs with MDR1 mutation. (For study results, see label indica-tions for specific trademark products.)

‒ Example: The ivermectin monthly dose of 6 µg/kg for heartworm pre-vention is ≈20 times lower than the dose of ivermectin that could cause neurologic toxicity in dogs with MDR1 mutation (anecdotal).2,8,21

‒ Note: Doses of ivermectin used to treat mange (300-600 µg/kg) should not be used in dogs with heterozy-gous or homozygous MDR1 mutation.

Is Pesticide Use a Problem in Affected Animals?Abamectin (similar to ivermectin) is the active ingredient in many pesticides licensed for both indoor (eg, ant bait, roach bait) and outdoor (eg, premise sprays) use. These products can cause severe neurologic toxicity in dogs with MDR1 mutation.8 Animals with the MDR1 mutation should avoid contact with these products. Clinical signs in

• Most of the nearly 100 drugs that could fit criteria cited in these studies do not cause toxicity in animals with P-glycoprotein dysfunction. Many (eg, cephalosporins, penicillins, tetracyclines, antihistamines, β-adrenergic antagonists) have 1 or more characteristics that allow for safe use in animals with P-glycopro-tein dysfunction, including:

– Wide therapeutic margin – Minimal neurologic toxicity – Alternate drug clearance

mechanisms – Ability to be pumped by a different

drug transporter

TABLE 2

APPROXIMATE FREQUENCY OF MDR1 GENE MUTATIONS8,16,18

Breed Approximate Frequency

Collie 70%

Longhaired whippet 65%

Australian shepherd dog 50%

Miniature Australian shepherd dog 50%

McNab shepherd dog 30%

Silken windhound 30%

English shepherd dog 15%

Shetland sheepdog 15%

German shepherd dog 10%

Herding breed cross 10%

Mixed breed 5%

Old English sheepdog 5%

Border collie <5%

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involves either decreasing drug doses or considering alternate drugs. Failure to consider MDR1 genotype or drug-drug interactions that result in P-glycopro-tein dysfunction can have devastating consequences. MDR1 genotyping for the respective canine or feline MDR1 muta-tions is available from the Washington State University VCPL. n

dogs are similar to those observed with ivermectin toxicosis. The author is unaware of specific abamectin toxicities in cats, but clinical signs are expected to be similar to those seen with ivermectin.

ConclusionPharmacologic treatment of dogs or cats with P-glycoprotein dysfunction

LEADING RESEARCH & UPDATESThe Veterinary Clinical Pharmacology Laboratory (VCPL) at Washington State University discovered the MDR1 mutation in both dogs and cats.2,6 This laboratory continues to lead research efforts in determining which drugs should be avoided in animals with P-glycoprotein dysfunction and provides key information on its website (vcpl.vetmed.wsu.edu), including an up-to-date list of drugs known to cause toxicity in animals with P-glycoprotein dysfunction and with drugs that should be used cautiously in animals with P-glycoprotein dysfunction. A list of peer-reviewed research articles from veterinary and scientific journals, as well as veterinary textbooks that provide supportive and more detailed information, is also available on the website.22-24

1d Example of a mixed-breed dog with MDR1 mutant/mutant genotype. Physical

characteristics of herding breeds are not always apparent.

References1. Schinkel AH, Wagenaar E, van Deemter L, Mol CA,

Borst P. Absence of the Mdr1A P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporine A. J Clin Invest. 1995;96(4):1698-1705.

2. Mealey KL, Bentjen SA, Gay JM, Cantor GH. Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics. 2001;11(8):727-733.

3. Mealey KL, Greene S, Bagley R, et al. P-glycoprotein contributes to the blood-brain but not blood-cerebrospinal fluid barrier in a spontaneous canine p-glycoprotein knockout model. Drug Metab Dispos. 2008;36(6):1073-1079.

4. Coelho JC, Tucker R, Mattoon J, et al. Biliary excretion

of technetium-99m-sestamibi in wild-type dogs and in dogs with intrinsic (ABCB1-1Δ mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency. J Vet Pharmacol Ther. 2009;32(5):417-421.

5. Mealey KL, Fidel J, Gay JM, Impellizeri JA, Clifford CA, Bergman PJ. ABCB1-1D Polymorphism can predict hematologic toxicity in dogs treated with vincristine. JVIM. 2008;22(4):996-1000.

6. Mealey KL, Burke NS. Identification of a nonsense mutation in feline ABCB1. J Vet Pharmacol Ther. 2015;38(5):429-433.

7. Mealey KL, Fidel J. P-glycoprotein mediated drug interactions in animals and humans with cancer. JVIM. 2015;29(1):1-6.

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ASK THE EXPERT h GENETICS / PHARMACOLOGY h PEER REVIEWED

8. Mealey KL. Unpublished observations, clinical data, and ongoing clinical laboratory research; small animal medicine and research, Washington State University, accumulated clinical/laboratory evidence as of March 2016.

9. Krugman L, Bryan JN, Mealey KL, Chen A. Vincristine-induced central neurotoxicity in a collie homozygous for the ABCB1Δ mutation. J Small Anim Pract. 2012;53(3):185-187.

10. Barbet JL, Snook T, Gay JM, Mealey KL. ABCB1-1Δ (MDR1-1Δ) genotype is associated with adverse reactions in dogs treated with milbemycin oxime for generalized demodicosis. Vet Dermatol. 2009;20(2):111-114.

11. Sartor LL, Bentjen SA, Trepanier L, Mealey KL. Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. JVIM. 2004;18(1):117-118.

12. Elmshäuser S, Straehle LC, Kranz J, Krebber R, Geyer J. Brain penetration of emodepside is increased in P-glycoprotein-deficient mice and leads to neurotoxicosis. J Vet Pharmacol Ther. 2015;38(1);74-79.

13. Deshpande D, Hill KE, Mealey KL, Chambers JP, Gieseg MA. The effect of the canine ABCB1-1Δ mutation on sedation after intravenous administration of acepromazine. JVIM. 2016;30(2):636-641

14. Schrickx JA. Spinosad is a potent inhibitor of canine P-glycoprotein. Vet J. 2014;200(1):195-196.

15. Comfortis (spinosad) Chewable Tablets (package insert). Indianapolis, IN; Elanco Animal Health; 2009.

16. Neff MW, Robertson KR, Wong AK, et al. Breed distribution and history of

canine MDR1-1Δ, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci USA. 2004;101(32):11725-11730.

17. Didziapetris R, et al. Classification analysis of P-glycoprotein substrate specificity. Journal of Drug Targeting. 2003;11(7).

18. Mealey KL, Meurs KM. Breed distribution of the ABCB1-1D (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. JAVMA. 2008;233(6):921-924.

19. Evans J, Levesque D, Knowles K, Longshore R, Plummer S. Diazepam as a treatment for metronidazole toxicosis in dogs: a retrospective study of 21 cases. JVIM. 2003;17(3):304-310.

20. Heartgard Plus (ivermectin/pyrantel) Chewables for Dogs (package insert). Duluth, GA; Merial; 2010.

21. Nelson OL, Carsten E, Bentjen SA, Mealey KL. Ivermectin toxicity in an Australian shepherd dog with MDR1 mutation associated with ivermectin sensitivity in collies. JVIM. 2003; 17(3):354-356.

22. Mealey KL. Pharmacogenomics. In: Riviere JE, Papich MG, eds. Veterinary Pharmacology and Therapeutics. 9th ed. Ames, IA: Wiley-Blackwell; 2009:1313-1321.

23. Mealey KL. Ivermectin toxicosis. In: Cote E, ed. Clinical Veterinary Advisor: Dogs and Cats. 3rd ed. St. Louis, MO: Elsevier; 2015:625-627.

24. Mealey KL. Ivermectin: Macrolide antiparasitic agents. In: Peterson ME, Talcott PA, eds. Small Animal Toxicology. 3rd ed. St. Louis, MO: Elsevier Saunders; 2006:601-608.

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