PT  - JOURNAL ARTICLE
AU  - Mealey, Katrina L.
AU  - Greene, Stephen
AU  - Bagley, Rodney
AU  - Gay, John
AU  - Tucker, Russ
AU  - Gavin, Patrick
AU  - Schmidt, Kari
AU  - Nelson, Frederick
TI  - P-Glycoprotein Contributes to the Blood-Brain, but Not Blood-Cerebrospinal Fluid, Barrier in a Spontaneous Canine P-Glycoprotein Knockout Model
AID  - 10.1124/dmd.107.018978
DP  - 2008 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 1073--1079
VI  - 36
IP  - 6
4099  - http://dmd.aspetjournals.org/content/36/6/1073.short
4100  - http://dmd.aspetjournals.org/content/36/6/1073.full
SO  - Drug Metab Dispos2008 Jun 01; 36
AB  - 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