MDR1


WASHINGTON STATE UNIVERSITY ARTICLE JULY 2013

Many herding breed dogs (the most commonly affected in the UK are: All breeds of Collie, Shetland Sheepdog, GSD and, Australian Shepherd dogs - including cross breeds) have a genetic predisposition to adverse drug reactions involving over a dozen different drugs.

The most serious adverse drug reactions involve several antiparasitic agents, Ivermectin, Milbemycin (and related drugs), the antidiarrheal agent Loperamide (Imodium), and several anticancer drugs (Vincristine, and Doxorubicin, plus several others). These drug sensitivities result from a mutation in the multidrug resistance gene (MDR1 gene).

A test distinguishes between clear, carrier and affected dogs. Clear dogs have no copies of the mutant gene responsible for the condition and will neither develop the condition nor pass the gene on to their offspring. Carrier dogs have one copy of the normal gene and one copy of the mutant gene, they will not develop the condition, but will pass a mutant gene on to approximately half of their offspring. Affected dogs have two copies of the mutant gene that causes the condition, and therefore, will react adversely to certain drugs.

When considering the use of macrocyclic lactones such as ivermectin or moxidectin in dogs, vets have followed the adage, “white feet, don’t treat.” This refers to the known sensitivity of Scotch collies (both rough and smooth) to neurotoxicity when administered these drugs at higher than label doses. But the adage has also been applied to many other herding breeds and has prevented vets from using these drugs in situations where they would have been ideal. The neurotoxicity was attributed to a leaky “blood-brain barrier” in susceptible dogs. Recent developments in the molecular mechanisms of this phenomenon have opened a new frontier in the area of pharmacogenetics — drug disposition determined by the animal’s genotype. So “white feet, don’t treat” is no longer the practice standard; now it is “white feet, test to see if you can treat.”

Recognizing that the collies and other herding breeds that were sensitive to ivermectin were similar to the mdr knockout mice, Dr. Katrina Mealey at Washington State University, College of Veterinary Medicine, demonstrated that a deletion mutation of the mdr gene was present in ivermectin-sensitive collies

Test results from Laboklin will automatically be sent to the Kennel Club for inclusion on its database

Results from other laboratories may be included on the database upon owner submission and request – please email hbs@thekennelclub.org.uk for further information.

The current list of drugs (as at December 2012) that cause sensitivity to dogs with the MDR1 mutation is as below,
but please refer to LABOKLIN for up to date information as new drugs are often added.

There are many other drugs that have been shown to be pumped by human P-glycoprotein (the protein encoded by the MDR1 gene), but data is not yet available with regard to their effect in dogs with the MDR1 mutation. Please also refer to a list maintained by Washington State University HERE

DOWNLOADS (pdf documents)

MDR1 CHECK LIST

LETTER TO TAKE TO VET

MDR1 FACTSHEET

ROUGH COLLIE BREED COUNCIL NOTES


COLLIE GENERAL ANESTHESIA

KATRINA MEALEY VETERINARY CONFERENCE

LIST OF DRUGS FOR PRINTING

TREATMENT OF MDR1

WSAVA DISEASE COMMITTEE


LIST OF DRUGS THAT CAUSE SENSITIVITY TO DOGS WITH MDR1 MUTATION

Class A DO NOT use these drugs in dogs with the MDR1 Gene Defect

Ivermectine substances "Anti parasites": (Diapec®, Ecomectin®, Equimax®, Eqvalan®, Ivomec®, Noromectin®, Paramectin®, Qualimec®, Sumex®, Virbamec®) 

Doramectine substances "Anti parasites":  (Dectomax® )

Loperamide substances "ant diarrheal ": (Imodium®)

Moxidectine substances "Anti Parasites" (Cydectin®, Equest®) 

(Flagyl )

Class B

Use only under close control of veterinarian

Cytostatics  "Chemotherapy": (Vinblastine, Vincristine, Doxorubicine, Paclitaxel, Docetaxel, Methotrexat, Vincristine)

Immunosuppressive: (Cyclosporine A)

Heart glycosides: (Digoxine, Methyldigoxine)

Opioids: (Morphium)

Antiarrhythmics: (Verapamil, Diltiazem, Chinidine)
 

Antiemetics (Ondansetron, Domperidon, Metoclopramide )
 

Antibiotics (Sparfloxacin, Grepafloxacin, Erythromycin)
 

Antihistamin (Ebastin)
 

Glucocorticoid (Dexamethason)

Acepromazine (tranquilizer and pre-anesthetic agent) *

Butorphanol "analgesic and pre-anesthetic agent" *

Other drugs: Etoposide, Mitoxantrone, Ondansetron, Paclitaxel, Rifampicin 

Class C Can be used only in the permitted application form and dose Selamectin (Stronghold®), Milbemax®  and Advocate® .

 

Sire

  Dam Offspring
       
Clear
x
Clear
100% Clear
       
clear
x
carrier
50%  Clear + 50% carriers
       
clear
x
affected
100% carriers
       
carrier
x
Clear
50%  Clear + 50% carriers
       
carrier
x
carrier
25% clear + 25% affected + 50% carriers
       
carrier
x
affected
50% carriers + 50% affected
       
affected
x
Clear
100%  carriers
       
affected
x
carrier
50% carriers + 50% affected
       
affected
x
affected
100% affected

 


Clear - Genotype: N / N [ Homozygous normal ]

The dog is noncarrier of the mutant gene.

The dog will never develop MDR1 Gene Defect / Ivermectin Sensitivity * and therefore it can be bred to any other dog.

 

Carrier - Genotype: N / MDR1 [ Heterozygous ]

The dog carries one copy of the mutant gene and one copy of the normal gene.

The dog may develop MDR1 Gene Defect / Ivermectin Sensitivity.
Since it carries the mutant gene, it can pass it on to its offspring with the probability of 50%.

 

Affected - Genotype: MDR1 / MDR1 [ Homozygous mutant ]

 The dog carries two copies of the mutant gene and therefore it will pass the mutant gene to its entire offspring. The dog will develop MDR1 Gene Defect / Ivermectin Sensitivity * and will pass the mutant gene to its entire offspring

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