RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 1073
OP 1079
DO 10.1124/dmd.107.018978
VO 36
IS 6
A1 Mealey, Katrina L.
A1 Greene, Stephen
A1 Bagley, Rodney
A1 Gay, John
A1 Tucker, Russ
A1 Gavin, Patrick
A1 Schmidt, Kari
A1 Nelson, Frederick
YR 2008
UL http://dmd.aspetjournals.org/content/36/6/1073.abstract
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