P-glycoprotein contributes to the blood-brain, but not blood-cerebrospinal fluid, barrier in a spontaneous canine p-glycoprotein knockout model
| Autor: | Katrina L. Mealey, Stephen Greene, Rodney Bagley, John Gay, Russ Tucker, Patrick Gavin, Kari Schmidt, Frederick Nelson |
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| Rok vydání: | 2008 |
| Předmět: |
Drug
Male Technetium Tc 99m Sestamibi Loperamide media_common.quotation_subject Central nervous system Pharmaceutical Science Pharmacology Cerebrospinal fluid Dogs Parenchyma Medicine Animals ATP Binding Cassette Transporter Subfamily B Member 1 P-glycoprotein media_common biology business.industry Cns depression medicine.drug_physiologic_effect Brain Central Nervous System Depressants medicine.anatomical_structure Opioid Blood-Brain Barrier Immunology Models Animal biology.protein Female business medicine.drug |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 36(6) |
| ISSN: | 1521-009X |
| Popis: | 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 (ABCB1-1Delta) 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. ABCB1-1Delta 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 (99m)Tc-sestamibi at the blood-brain barrier and blood-CSF barrier. |
| Databáze: | OpenAIRE |
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