title: Establishment of a cell line for assessing drugs as canine P-glycoprotein substrates: proof of principle.
abstract: P-glycoprotein (P-gp), encoded by the ABCB1 (MDR1) gene, dramatically impacts drug disposition. P-gp is expressed in the intestines, biliary canaliculi, renal tubules, and brain capillaries where it functions to efflux substrate drugs. In this capacity, P-gp restricts oral absorption, enhances biliary and renal excretion, and inhibits central nervous system entry of substrate drugs. Many drugs commonly used in veterinary medicine are known substrates for canine P-gp (vincristine, loperamide, ivermectin, others). Because these drugs have a narrow therapeutic index, defective P-gp function can cause serious adverse drug reactions due to enhanced brain penetration and/or decreased clearance. P-gp dysfunction in dogs can be intrinsic (dogs harboring ABCB1-1Δ) or acquired (drug interactions between a P-gp inhibitor and P-gp substrate). New human drug candidates are required to undergo assessment for P-gp interactions according to FDA and EMA regulations to avoid adverse drug reactions and drug-drug interactions. Similar information regarding canine P-gp could prevent adverse drug reactions in dogs. Because differences in P-gp substrates have been documented between species, one should not presume that human or murine P-gp substrates are necessarily canine P-gp substrates. Thus, our goal was to develop a cell line for assessing drugs as canine P-gp substrates.
authors.affiliation: Program in Individualized Medicine (PrIMe), College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Mealey
authors.affiliation: Program in Individualized Medicine (PrIMe), College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dassanayake
authors.affiliation: Program in Individualized Medicine (PrIMe), College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Burke
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D004285:Dogs / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007559:Ivermectin; D051379:Mice; D013379:Substrate Specificity
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007559:Ivermectin