%0 Journal Article %A Katrina L. Mealey %A Stephen Greene %A Rodney Bagley %A John Gay %A Russ Tucker %A Patrick Gavin %A Kari Schmidt %A Frederick Nelson %T P-Glycoprotein Contributes to the Blood-Brain, but Not Blood-Cerebrospinal Fluid, Barrier in a Spontaneous Canine P-Glycoprotein Knockout Model %D 2008 %R 10.1124/dmd.107.018978 %J Drug Metabolism and Disposition %P 1073-1079 %V 36 %N 6 %X 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 (ABCB1-1Δ) 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. ABCB1-1Δ 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 99mTc-sestamibi at the blood-brain barrier and blood-CSF barrier. The American Society for Pharmacology and Experimental Therapeutics %U https://dmd.aspetjournals.org/content/dmd/36/6/1073.full.pdf