title: The ABCB1-1Delta mutation is not responsible for subchronic neurotoxicity seen in dogs of non-collie breeds following macrocyclic lactone treatment for generalized demodicosis.
abstract: P-glycoprotein (P-gp), encoded by the multiple drug resistance gene ABCB1 (also known as MDR1), is an integral component of the blood brain barrier crucial in limiting drug uptake into the central nervous system. Altered expression or function of P-gp, as seen in dogs of the collie lineage homozygous for the nt228(del4) mutation of the ABCB1 gene (ABCB1-1Delta), can result in potentially fatal neurotoxicosis, especially following administration of systemic macrocyclic lactones (SML). Occasionally, dogs from unrelated breeds develop subchronic signs of neurotoxicity when receiving SML to treat generalized demodicosis. It is possible that these dogs are heterozygous carriers of the ABCB1-1Delta mutation, resulting in decreased P-gp activity and central neurotoxicosis. Cheek swabs were collected from 28 dogs with generalized demodicosis that had shown subchronic signs of neurotoxicity following daily oral administration of ivermectin or other SML. Ten of these animals received concurrent systemic treatment with other confirmed or putative P-gp substrates. After DNA extraction, the relevant portion of the ABCB1 gene was amplified by polymerase chain reaction, and sequenced. Twenty-seven dogs were homozygous normal while one dog was heterozygous for the ABCB1-1Delta mutation. Therefore, with the exception of one dog, the observed neurotoxicity could not be attributed to the ABCB1-1Delta mutation. Possible explanations for the adverse reactions observed include pharmacological interactions (administration of SML with other P-gp substrates or inhibitors), excessively high doses, polymorphisms in P-gp expression, uncharacterized mutations in the ABCB1 gene or in another gene, or phenomena unrelated to the SML-P-gp interaction.
authors.affiliation: Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montreal, St-Hyacinthe, Québec, Canada.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bissonnette
authors.forename: Manon
authors.initials: M
authors.lastname: Paradis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Daneau
authors.forename: David W
authors.initials: DW
authors.lastname: Silversides
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D000935:Antifungal Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001483:Base Sequence; D003881:Dermatomycoses / Q000188:drug therapy / Q000662:veterinary; D004283:Dog Diseases / Q000139:chemically induced* / Q000235:genetics; D004285:Dogs; D005260:Female; D020022:Genetic Predisposition to Disease; D007783:Lactones / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D020258:Neurotoxicity Syndromes / Q000235:genetics / Q000662:veterinary*; D027361:Organic Anion Transporters / Q000235:genetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D007783:Lactones; D027361:Organic Anion Transporters