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Multi-Drug
Resistance 1 (MDR1)
is a semi-dominant mutation that causes a clinical sensitivity to a
number of common drugs (including Ivermectin) by impairing the transport of
those drugs out of the canine brain allowing for a toxic buildup of the drugs
upon administration of sufficient doses, which can lead to neurological
dysfunction and death.

Ivermectin
toxicity in Collies was first described in 1983 (Preston, 1983; Seward, 1983).
Doses that are just a small part of the dose required to cause Ivermectin
toxicity in other dogs, in Collies causes neural toxicity (Tranquilli et al.,
1987; Paul et al., 1987). Many investigations were done, but cause of this
susceptibility was not cleared until a mutation in MDR1 was discovered.
Ivermectin sensitivity in Collies has been associated with homozygous expression
of a  mutation in MDR1 gene.

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This
mutation (ATAG) involves four-base-pair frame-shift deletion (nt230del4 on
chromosome 14, which generates a premature stop codon, thus preventing
synthesis of the complete protein product, but rather truncated, nonfunctional
protein (Mealey et al., 2001). Two years later, this work was confirmed by
other investigators (Roulet et al., 2003). MDR1 gene has also been referred to
as ABCB1 based on the nomenclature of the ATP-binding cassette (ABC)
transporter family (Dean, 2005).

P-glycoprotein,
the product of the MDR1 gene, is an important component of blood-brain barrier
(Kim et al., 1998; Jonker et al., 1999; Fromm, 2002;). This protein is an
ATP-dependent drug transport pump which is expressed on the luminal membrane of
endotelial cells of the brain capillaries. It protects transportation of
different subtrates, including ivermectin, from brain tissue into the capillary
volumen, which results in lower brain concentrations of drugs that are
substrates for P-glycoprotein. Other subtrates include doramectin, moxidectin,
milbemycin oxime, loperamide, the antiemetic ondansetron, digoxin,
chemotherapeutic drugs including doxorubicin, vincristine and vinblastine, as
well as many other drugs (Schinkel et al., 1994; Sartor et al., 2004; Geyer et
al., 2005a, 2007; Mealey et al., 2008; Barbet et al., 2009). P-gp is expressed
in different mammalian tissues such as the luminal membrane of proximal tubules
in the kidney, the brush border membrane of epithelial cells in the intestinal
tract and the canalicular membrane of liver hepatocytes (Thiebaut et al.,
1987). Oral drug bioavailability is diminished because of the apical/luminal
expression of P-glycoprotein and drugs are eliminated into urine and bile
(Fromm, 2000).

Two
mutant alleles of this gene are needed to display the ivermectin-sensitive
phenotype and those dogs are susceptible to toxicity caused by other substrates
of P-glycoprotein as well (Sartor et al., 2004). MDR1 knockout mice have proved
that lack of P-glycoprotein leads to increased accumulation of certain drugs in
brain with undesired neurologic effects (Schinkel et al., 1994). Other
substrates for P-glycoprotein that can cause toxicity in affected dogs are
vinblastine, vincristine, doxorubicin, ondansetron and other macrolide
anthelmintics.

MDR1 in herding
breeds is caused by a 4 base pair deletion (ATAG) in the ABCB1 gene on
chromosome 14. Dogs that are homozygous for the deletion mutation display the
ivermectin-sensitive phenotype, while those that are homozygous normal or
heterozygous do not display increased sensitivity to ivermectin (Washington
2001).

To this date, MDR1
genotyping studies from different countries have shown that apart from the
Collie, other dog breeds are affected by this mutation, including Shetland
Sheepdog, Australian Shepherd, English Shepherd, Old English Sheepdog, White
Shepherd, German Shepherd, Wäller, Longhaired Whippet, McNab and Silken
Windhound has been described in Collie-related breeds (Geyer et al., 2005b;
Neff et al., 2004; Mealey and Meurs, 2008).

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