Received for publication September 26, 2007.
Revised March 6, 2008.
Accepted for publication March 7, 2008.

P-glycoprotein contributes to the blood-brain, but not blood-CSF, barrier in a spontaneous canine P-glycoprotein knockout model

Abstract

P-glycoprotein is considered to be as a major factor impeding effective drug therapy for many CNS diseases. 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 (ABCB1-1) 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. ABCB1-1 dogs experienced CNS depression following loperamide administration whereas ABCB1 wildtype 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.

Key words: ABC transporters, blood-brain barrier, blood-CNS transport, p-glycoprotein, pharmacogenetics