P-Glycoprotein Contributes to the Blood-Brain, but Not Blood-Cerebrospinal Fluid, Barrier in a Spontaneous Canine P-Glycoprotein Knockout Model
- 10 March 2008
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 36 (6), 1073-1079
- https://doi.org/10.1124/dmd.107.018978
Abstract
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.Keywords
This publication has 31 references indexed in Scilit:
- Clinical Relevance of P-Glycoprotein in Drug TherapyDrug Metabolism Reviews, 2003
- Characterization of a Novel 99mTc-Carbonyl Complex as a Functional Probe of MDR1 P-Glycoprotein Transport ActivityMolecular Imaging, 2002
- Blood-brain barrier biology and methodologyJournal of NeuroVirology, 1999
- EDITORIALMethods, 1998
- P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs.JCI Insight, 1996
- Comparisons of P‐glycoprotein expression in isolated rat brain microvessels and in primary cultures of endothelial cells derived from microvasculature of rat brain, epididymal fat pad and from aortaFEBS Letters, 1995
- Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A.JCI Insight, 1995
- Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugsCell, 1994
- Dose-Related Changes in the Rate of CSF Formation and Resistance to Reabsorption of CSF During Administration of Fentanyl, Sufentanil, or Alfentanil in DogsJournal of Neurosurgical Anesthesiology, 1991
- Specialized Localization of P‐Glycoprotein Recognized by MRK 16 Monoclonal Antibody in Endothelial Cells of the Brain and the Spinal CordJapanese Journal of Cancer Research, 1990