unlikely that the efficacy of AEDs in this study (non– P-gp substrates or weak P-gp substrates) was affected by P-gp expression at the blood-brain barrier in dogs.
AED Antiepileptic drug
ATP-binding cassette drug transporters, such as P-gp. 1
P-glycoprotein is a membrane-bound efflux pump that is localized in tissues with a barrier function, such as the intestines, blood-brain barrier, bile canaliculi, and renal tubules. It is the
P-glycoprotein is a transmembrane efflux protein in the ATP-binding cassette family of transport proteins. It is encoded by the MDR1 gene, which is currently termed ABCB1 . Humans and dogs have only 1 form of the ABCB1 gene, whereas mice have
expression changes in p-glycoprotein (p-gp) observed in human dementia patients to CCD patients.
To plot and quantify the longitudinal progression of behavioral deviations and biomarker values that pinpoint the onset of CCD.
Achieving these goals in
to hypothesize that the administration of spinosad increases systemic exposure to ivermectin.
It is known that there is increased systemic exposure to ivermectin in dogs with impaired P-glycoprotein function. 4 The most commonly known and examined
expression of the transfected vector from the expression of intrinsic P-gp because P-gp represents one of the natural defenses of most cells to toxic compounds. P-glycoprotein was strongly expressed 48 hours after transfection of the pLNC-cMDR1 clone into COS
overexpression in drug-resistant tumor cells, ABCB1 is primarily expressed in cells of intestinal, hepatic, renal, and brain tissue. 3,4,8–10 P-glycoprotein contributes to the barrier function of these organs and protects the cells by actively extruding
expressed in high concentrations on epithelial cells of the liver, renal tubules, and most secretory organs; the capillary endothelium of the bloodbrain and blood-testis barriers; and nodal lymphocytes. P-glycoprotein extrudes large, hydrophobic, uncharged
Objective—To determine the frequency of the MDR1
gene mutation (polymorphism) associated with ivermectin
sensitivity in a sample population of Collies in
Washington and Idaho.
Animals—40 healthy client-owned Collies.
Procedure—A blood sample (8 ml) was collected
from each dog and used for RNA extraction. Reverse
transcriptase was used to generate MDR1 cDNA.
Polymerase chain reaction (PCR) primers were
designed to amplify a 1,061-base pair region of the
MDR1 gene. The PCR products were sequenced to
determine whether the Collies had 0, 1, or 2 mutant
alleles. Pedigrees of some dogs were available for
analysis to determine relatedness of affected dogs.
Results—Of the 40 Collies, 9 (22%) were homozygous
for the normal allele (normal), 17 (42%) were
heterozygous (carrier), and 14 (35%) were homozygous
for the mutant allele (affected). Pedigree analysis
revealed that some, but not all, affected dogs
were related to each other within the 4 most recent
Conclusions and Clinical Relevance—A high percentage
of a sample population of Collies in
Washington and Idaho are affected or carriers of the
mutant MDR1 allele associated with ivermectin sensitivity.
A similar frequency of this mutation may be
detected in dogs from other geographic areas.
Pharmacologic treatment with ivermectin, loperamide,
vincristine, and other drugs that are substrates
of P-glycoprotein, the MDR1 gene product,
may result in neurologic toxicosis in a high percentage
of Collies. (Am J Vet Res 2002;63:479–481)