title: P-glycoprotein contributes to the blood-brain, but not blood-cerebrospinal fluid, barrier in a spontaneous canine p-glycoprotein knockout model.
abstract: P-glycoprotein is considered to be a major factor impeding effective drug therapy for many diseases of the central nervous system (CNS). Thus, efforts are being made to gain a better understanding of P-glycoprotein's role in drug distribution to brain parenchyma and cerebrospinal fluid (CSF). The goal of this study was to validate and introduce a novel P-glycoprotein-deficient (ABCB1-1Delta) canine model for studying P-glycoprotein-mediated effects of drug distribution to brain tissue and CSF. CSF concentrations of drug are often used to correlate efficacy of CNS drug therapy as a surrogate for determining drug concentration in brain tissue. A secondary goal of this study was to investigate the validity of using CSF concentrations of P-glycoprotein substrates to predict brain tissue concentrations. Loperamide, an opioid that is excluded from the brain by P-glycoprotein, was used to confirm a P-glycoprotein-null phenotype in the dog model. ABCB1-1Delta dogs experienced CNS depression following loperamide administration, whereas ABCB1 wild-type dogs experienced no CNS depression. In summary, we have validated a novel P-glycoprotein-deficient canine model and have used the model to investigate transport of the P-glycoprotein substrate (99m)Tc-sestamibi at the blood-brain barrier and blood-CSF barrier.
authors.affiliation: Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-6610, USA. kmealey@vetmed.wsu.edu
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Mealey
authors.forename: Stephen
authors.initials: S
authors.lastname: Greene
authors.forename: Rodney
authors.initials: R
authors.lastname: Bagley
authors.forename: John
authors.initials: J
authors.lastname: Gay
authors.forename: Russ
authors.initials: R
authors.lastname: Tucker
authors.forename: Patrick
authors.initials: P
authors.lastname: Gavin
authors.forename: Kari
authors.initials: K
authors.lastname: Schmidt
authors.forename: Frederick
authors.initials: F
authors.lastname: Nelson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D008139:Loperamide / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D017256:Technetium Tc 99m Sestamibi / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002492:Central Nervous System Depressants; D008139:Loperamide; D017256:Technetium Tc 99m Sestamibi