Multi Drug Resistance (MDR1 dog)
The MDR1 defect (also called ABCB1-1Δ) is a hereditary condition in dogs caused by a 4-base-pair deletion (nt230(del4) in the ABCB1 gene. This mutation leads to the complete loss of function of P-glycoprotein (P-gp) – a crucial efflux transporter in the blood-brain barrier and other tissues. Without this protective mechanism, certain drugs (e.g., ivermectin, doramectin, moxidectin, loperamide) can enter the central nervous system unchecked, causing neurotoxic reactions.
Risk is highly breed-dependent: the mutation is common in Collies, Australian Shepherds, and Shetland Sheepdogs, but very rare in the general canine population (allele frequency ~0.2%). Genetic testing is strongly recommended for at-risk breeds before administering potentially dangerous medications.
Clinical Signs
Dogs homozygous for the mutation (mdr1/mdr1) can develop severe neurological symptoms even at therapeutic doses of certain P-gp substrate drugs:
- Ataxia
- Lethargy
- Tremors
- Seizures
- Mydriasis
- Blindness
- Coma
Heterozygous dogs (N/mdr1) are usually asymptomatic but may still react under certain circumstances – for example, with high dosages or with specific drugs such as vincristine.
Pathogenesis of MDR 1
The mutated ABCB1 gene produces a truncated, non-functional P-glycoprotein. Normally, this ATP-dependent transporter pumps lipophilic xenobiotics out of cells, especially at the blood-brain barrier, thereby preventing neurotoxic compounds from entering the brain.
If P-gp is absent or defective, these drugs accumulate in the central nervous system and other protected tissues. In animal models, P-gp deficiency increases brain ivermectin concentrations by up to 87-fold, leading to 50–150 times greater toxicity.
Gene, Mutation, and DNA Test
- Gene: ABCB1 (formerly MDR1)
- Mutation: nt230(del4), 4-bp deletion in exon 4, causing a frameshift and premature stop codon
- Inheritance: Autosomal recessive
- DNA Testing Methods: qPCR with dual probes or PCR + Sanger sequencing
- Genotypes:
- N/N: Wild type – no increased sensitivity
- N/mdr1: Carrier – potentially increased sensitivity
- mdr1/mdr1: Affected – high risk of drug toxicity
Affected breeds, Medications and Risk Categories
Die ABCB1‑1Δ‑Mutation tritt vor allem in klassischen „Herding Breeds“ häufig auf: Collies, Australian Shepherds und Shetland Sheepdogs. Neuere Studien weisen darauf hin, dass in den anderen Rassen das gelegentliche Vorkommen auf einzelne Einkreuzungen der Hochrisiko-Rassen zurückzuführen ist.
| Category | Example Drugs | Comments |
|---|---|---|
| Avoid | High-dose macrocyclic lactones: ivermectin > 100 µg/kg, doramectin, moxidectin > 3 µg/kg, selamectin (overdose) Loperamide Acepromazine Butorphanol Chemotherapeutics: vincristine, vinblastine, doxorubicin, paclitaxel, docetaxel | Life-threatening neurotoxicity possible. Do not use in mdr1/mdr1. Use reduced dose with great caution in N/mdr1. |
| Use with caution / dose adjustment | Milbemycin oxime (high dose) Cyclosporin A, tacrolimus Digoxin, quinidine Ondansetron, verapamil Certain fluoroquinolones: sparfloxacin, grepafloxacin | Reduce dose and monitor closely. Risk increases with dose and in mdr1/mdr1 genotype. |
| Safe at standard doses | Low-dose macrocyclic lactones for heartworm prevention: ivermectin ≤ 6 µg/kg, moxidectin ≤ 3 µg/kg Non-P-gp substrates (e.g., most β-lactam antibiotics, NSAIDs, corticosteroids at moderate doses) | Applies only to MDR1; other sensitivities may still occur. Always check current drug information.ezogen auf MDR1. Andere Unverträglichkeiten möglich. Immer aktuelle Fachinfo prüfen. |
Genotyp und Laborbefund
Genotype: N/N = normal , free - Wild type
The dog has the wild-type variant of the mutation examined in both copies of the ABCB1 gene. There is no sensitivity to the problematic drugs caused by the mutation. The offspring of the animal examined will only inherit intact genetic material.
Genotype: N/mdr1 = heterozygous - potentially increased vulnerability
The dog has one copy of the gene that is affected by the mutation. This defective variant will be passed on to offspring with a 50% probability.
Carriers may show symptoms when given high doses of certain medications.
Genotype: mdr1/mdr1= homozygous variant - affected
Both copies of the ABCB1 gene carry the mutation, rendering its function unavailable. Medications that belong to the risk group are contraindicated or require a significant dose reduction (please refer to the online encyclopaedia for details). All offspring of the tested animal will inherit a defective copy.
Recommendations
Dogs of at-risk breeds should be tested for MDR1 before receiving high-risk drugs.
Even in other breeds and mixed breeds, testing can help avoid dangerous drug reactions. Breeding programs should avoid producing mdr1/mdr1 offspring while maintaining genetic diversity (e.g., only mate carriers to tested clear dogs).
Literature
Mealey, KL., Bentjen, SA., Gay, JM., Cantor, GH.: Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11:727-33, 2001. Pubmed reference: 11692082.
Mealey, K.L., Meurs, K.M.: Breed distribution of the ABCB1-1Delta (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J Am Vet Med Assoc 233:921-4, 2008. Pubmed reference: 18795852. DOI: 10.2460/javma.233.6.921.
Myers, M.J., Martinez, M., Li, F., Howard, K., Yancy, H.F., Troutman, L., Sharkey, M.: Impact of ABCB1 genotype in Collies on the pharmacokinetics of R- and S-fexofenadine. J Vet Pharmacol Ther 41:805-814, 2018. Pubmed reference: 30020547. DOI: 10.1111/jvp.12696.
Beckers E. et al. (2022) The prevalence of the ABCB1-1Δ variant in a clinical veterinary setting: The risk of not genotyping. PLoS ONE 17(8): e0273706. https://doi.org/10.1371/journal.pone.0273706
Weitere Informationen sind auf der Webseite Online Mendelian Inheritance in Animals verfügbar.