TY - JOUR T1 - P-Glycoprotein Contributes to the Blood-Brain, but Not Blood-Cerebrospinal Fluid, Barrier in a Spontaneous Canine P-Glycoprotein Knockout Model JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1073 LP - 1079 DO - 10.1124/dmd.107.018978 VL - 36 IS - 6 AU - Katrina L. Mealey AU - Stephen Greene AU - Rodney Bagley AU - John Gay AU - Russ Tucker AU - Patrick Gavin AU - Kari Schmidt AU - Frederick Nelson Y1 - 2008/06/01 UR - http://dmd.aspetjournals.org/content/36/6/1073.abstract N2 - 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 ER -