MDR1 in dogs: genetic drug sensitivity

Overview

MDR1 drug sensitivity results from an inherited gene variant that changes how a dog handles certain drugs. The variant is most common in herding breeds but also occurs in crossbreeds. However, the same medicines are not a problem for every dog with the variant in every situation. Risk is assessed according to the drug, the amount given and other medicines used at the same time.

There is no cure for the gene variant, so planning medication safety in advance is the basis of management. A positive genetic test does not mean your dog cannot receive medicines or have its other illnesses treated appropriately. Nor is every case of drug sensitivity caused by this variant.

Causes

A protective transporter does not work normally

The ABCB1 gene directs production of P-glycoprotein and determines its basic function. Normally, this transport protein helps remove drugs from the body after they are given. It also limits the entry of certain drugs and toxins into the brain and other organs. When it does not work properly, a drug may build up in tissues or enter the brain in sufficient quantities to cause poisoning.

In the well-known variant found in Collies, a segment of 4 base pairs is missing from the DNA. Dogs with two altered alleles produce a greatly shortened P-glycoprotein. The protein is less than 10% of the length of the normal amino acid chain. As a result, entry of drugs such as ivermectin into the central nervous system cannot be limited in the usual way.

The number of altered gene copies affects risk

A dog may have 1 or 2 copies of the variant, and drug sensitivity can be particularly marked in dogs with two copies. A dog with one copy can also develop drug poisoning, although the effects are usually milder. Combining several medicines can also increase the overall concentrations of individual drugs in the body. This interaction risk can occur even without the gene variant.

Risk factors

The variant occurs in both Rough and Smooth Collies. Other susceptible breeds include Australian Shepherds, Shetland Sheepdogs and Border Collies. Published indicative breed estimates put the proportion of Collies with the variant at about 70%. The corresponding estimate for Australian Shepherds is about 50%. For Shetland Sheepdogs, the indicative figure is about 15%. For Border Collies, it is less than 5%.

Being a crossbreed does not rule out the variant, and a dog need not look like a herding dog to carry it. Accidental exposure to a horse wormer containing ivermectin, for example, can cause a serious emergency.

Some anti-sickness medicines, such as maropitant and ondansetron, also need an individual treatment assessment when the variant is present.

This also applies to apomorphine, which is used to induce vomiting.

If the genetic status of a dog with Collie ancestry is unknown, treatment is planned cautiously to allow for possible drug sensitivity.

Typical symptoms

Drug poisoning may cause the following changes that you can notice at home.

• Your dog vomits after receiving a medicine.

• Your dog becomes weak or has difficulty using its legs normally.

• Movement becomes unsteady and coordination deteriorates.

• The muscles tremble or your dog is visibly shaking.

• Your dog has seizures or episodes of involuntary movements.

• Your dog cannot see normally or bumps into obstacles.

The pupils may dilate in ivermectin poisoning. With severe poisoning, a dog may fall into a coma, a state of deep unconsciousness.

Neurological adverse effects of drugs also include confusion: your dog may not recognise its surroundings or behave normally.

Complications and consequences

The toxic effects of a drug entering the brain can be life-threatening. Severe ivermectin poisoning can also suppress breathing. However, drug sensitivity itself does not prevent a normal life if high-risk medicines and interactions are taken into account. Some dogs with the variant have reduced stress hormone regulation, which may predispose them to relative adrenal insufficiency during serious illness.

The adverse effects of different drugs depend on how the transport protein contributes to their absorption, distribution and elimination. Risk may therefore change when another interacting medicine is added to your dog's existing treatment.

Diagnosis at the vet

Genetic testing identifies inherited susceptibility

A DNA test identifies the gene variant associated with drug sensitivity. The sample can be collected with a brush from cells inside the cheek or taken as a blood sample. DNA from cheek cells provides the same genetic information as DNA from blood cells. The sampling method therefore does not change which variant the test looks for.

A normal result is often recorded as +/+, meaning the dog does not have the variant tested for. A +/- result means the dog inherited the variant from only one parent. A -/- result means two altered gene copies and sensitivity to certain drugs. Laboratories may also use WT for the normal allele and MUT or M for the altered allele.

This test targets a particular gene variant and does not identify a dog's breed ancestry. Testing establishes an individual dog's genetic status; it cannot reliably be inferred from estimated breed ancestry. Even a normal result leaves open the possibility of other types of drug sensitivity.

A cheek sample must be free of food particles, so a clean sample is part of reliable collection. Do not touch the brush bristles with your fingers, and let the brushes dry before packing them. The identification details on the sample and submission form must match, as an unclearly labelled sample cannot be tested.

Sometimes the variant is only identified when an unusual response to a medicine in a young dog is investigated.

Treatment

Planning medicine use

When planning treatment, the vet may choose a different drug or adapt treatment to the genetic result. Sedating medicines such as acepromazine and butorphanol need particular consideration. Some cancer medicines also require individual assessment. Loperamide, a medicine for diarrhoea, is avoided in dogs with the variant because of its neurological adverse effects.

Certain combinations involving ketoconazole, ciclosporin or spinosad may increase the risk of adverse effects in other dogs too. Medicines authorised for heartworm prevention can also be used in dogs with drug sensitivity when the vet confirms a safe way to use that particular product. You cannot assume the same safety applies to another product containing the same active ingredient for a different purpose.

Treating poisoning in a dog with symptoms

A dog with an adverse drug reaction receives supportive care according to its symptoms. Supportive treatment for poisoning includes maintaining breathing and treating neurological signs when necessary. Dehydration and electrolyte disturbances are corrected according to the dog's condition. Treatment may be needed until the harmful substance has been metabolised and eliminated from the body.

After a recent exposure, the vet assesses whether absorption of the substance can still be reduced. Do not induce vomiting at home in a dog that is unsteady, having seizures or has reduced consciousness. Use of activated charcoal is decided case by case, according to the substance and whether the dog can swallow safely. Charcoal can cause a harmful rise in blood sodium.

Decisions about prescribing, stopping or changing medicines are made with your vet; do not alter treatment yourself on the basis of a genetic result.

Depending on the severity of poisoning, supportive care may also include pain relief and treatment of heart problems. Inappropriate activated charcoal treatment may increase the risk of aspiration, when material enters the airways, if a dog cannot swallow safely. A severely dehydrated dog, a dog in shock or one that is persistently vomiting needs a separate assessment before charcoal is given.

Activated charcoal binds substances that it is suitable for in the intestine, reducing their absorption into the body. Gastric lavage is considered only in exceptionally serious situations, with the airway protected and the dog under anaesthesia or appropriate sedation.

Prevention

Adverse drug effects are prevented by identifying the variant and avoiding medicines unsuitable for the dog. A crossbreed should also be tested before receiving a drug known to cause adverse effects in dogs with the variant.

For breeding, the parents' genetic results help assess the puppies' risk of inheriting the variant. When both parents are carriers, each puppy has a 25% chance of inheriting 2 altered copies. In the same mating, the chance of inheriting one altered copy is 50%. The chance of inheriting no altered copies is 25%.

Automatically excluding every dog with the variant from breeding is not recommended, because identified drug sensitivity can be managed.

When one parent has 2 altered copies and the other has a normal result, every puppy inherits one altered copy. Puppies from two parents tested as normal have a 100% chance of a normal result for the gene tested. In a carrier-to-normal mating, the chance of inheriting an altered copy is 50%. When both parents have 2 altered copies, their offspring have a 100% chance of inheriting the variant from both parents.

Important for dog owners

Keep the genetic test report and make sure the result appears in your dog's medical records. Show it during emergency visits and when attending a new practice. Keep an up-to-date list of all medicines your dog takes so that possible interactions can be checked when new treatment is planned.

Give the genetic result to your vet so that unsuitable medicines can be avoided or treatment adapted.

If you suspect accidental exposure, keep the product name, active ingredient, estimated amount and time of exposure. Store medicines out of your dog's reach at home and at the stables. Tell the vet about the genetic result before sedation, surgery, parasite treatment or starting a new long-term medicine.

Ivermectin intended for horses is one example of a product that can cause life-threatening poisoning if accidentally ingested by a drug-sensitive dog.

Make sure anyone temporarily caring for your dog gives medicines only according to its individual treatment plan. Bring a written medicine list even when the appointment seems to concern just one new symptom. Assessing interactions requires information about all current medicines.

Frequently asked questions

Is a dog with one altered copy safe from adverse drug effects?

No: a dog with one altered copy can also develop drug poisoning, although the effects are usually milder than in a dog with two copies. A +/- result indicates a carrier with a reduced ability to tolerate certain drugs.

Can a crossbreed have the MDR1 variant?

Yes: the variant has been found in many crossbreeds, some of which do not look like herding dogs. An individual dog's status is established by genetic testing rather than appearance. The test identifies this particular variant; it does not establish the proportions of different breeds in a dog's ancestry.

Can my dog have parasite treatment despite the variant?

Yes, suitable options exist: for example, authorised uses for heartworm prevention can be safe even for a drug-sensitive dog. However, safety depends on the particular product and how it is used. Do not change or stop treatment yourself; review the plan with your vet.

Can a dog recover from the gene variant?

There is no cure or specific antidote for the drug sensitivity associated with the variant. This does not mean constant illness: careful medicine selection and consideration of interactions allow a dog to live normally. Any drug poisoning is treated with supportive care according to the symptoms it causes.

Do all puppies in a litter have the same genetic result?

Not necessarily: when both parents are carriers, a puppy may have 2, 1 or no altered copies. One puppy's result therefore cannot establish the individual drug sensitivity of all its siblings. Both parents' genetic results are needed to assess the puppies' risk.