| P-glycoprotein-Based Loperamide-Cyclosporine Drug Interaction at the Rat Blood-Brain Barrier: Prediction from In Vitro Studies and Extrapolation to Humans. | |
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MedLine Citation:
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PMID: 22316009 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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We have shown that the rat can quantitatively predict the verapamil-cyclopsorine A (CsA) drug-drug interaction (DDI) at the human blood-brain barrier (BBB). In addition, the potency (EC50) of CsA to inhibit rat BBB P-gp can be predicted from in vitro studies in MDRI-transfected cells. To assess if these excellent agreements extend to other substrates, we determined the magnitude of P-gp-based DDI at the rat BBB between loperamide (Lop) or its metabolite, N-desmethyl Lop (dLop), and escalating CsA blood concentrations. The percent increase in the brain:blood Lop concentration ratio was described by the Hill equation, Emax=2000%, EC50=7.1 µM and γ=3.7. The potency (EC50) of CsA to inhibit P-gp at the rat BBB was independent of the substrate used (verapamil, Lop, or dLop). Like the verapamil-CsA DDI, the potency (EC50) of CsA to inhibit rat BBB P-gp could be predicted from studies in MDRI-transfected cells. When 11C-Lop was co-administered with a 10 mg/kg i.v. infusion of CsA 1yielding ~5.6 uM CsA blood concentration) to healthy volunteers, the brain distribution of 11C-radioactivity was increased by 110% 1. When corrected for diffusible Lop metabolite(s), this translates into an increase in 11C-Lop brain distribution of 457%. Based on our rat data, we estimated a remarkably similar value at 5.6 μM blood CsA concentration, 588% increase in Lop brain distribution. These data support our conclusion that the rat is a promising model to predict P-gp based DDI at the human BBB. |
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Authors:
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Peng Hsiao; Jashvant D Unadkat |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-2-8 |
Journal Detail:
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Title: Molecular pharmaceutics Volume: - ISSN: 1543-8392 ISO Abbreviation: - Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-2-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101197791 Medline TA: Mol Pharm Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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