| Quantitative investigation of the impact of P-glycoprotein inhibition on drug transport across blood-brain barrier in rats. | |
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MedLine Citation:
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PMID: 20962062 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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The magnitude of P-glycoprotein [(P-gp)/multidrug resistance protein 1 (MDR1)]-mediated drug-drug interaction (DDI) at the blood-brain barrier (BBB) in rats was estimated by in vitro-in vivo correlation (IVIVC). In in vitro studies, rat Mdr1a-expressing LLC-PK1 cells were examined for the evaluation of P-gp inhibitory activity using digoxin as a P-gp probe substrate. The in vitro K(i) value was calculated using a modified corrected flux ratio that reflects the P-gp function. In in vivo studies, digoxin with or without P-gp inhibitors was administered to rats by constant intravenous infusion to evaluate the effect of P-gp inhibition on digoxin transport to the brain under steady-state conditions. In the presence of elacridar, the brain-to-plasma concentration ratio (K(p,brain)) of digoxin was approximately 14 times the control value. However, no significant change in the K(p,brain) was observed in the presence of clinically used P-gp inhibitors, with the exception of cyclosporine A. A positive correlation was found between the in vivo K(p,brain) of digoxin and [I(,unbound)/K(i)] (where I(,unbound) is the unbound plasma concentration of P-gp inhibitors). Compounds with [I(,unbound)/K(i)] values of >1 increased K(p,brain) of digoxin in rats. In summary, we used a quantitative approach to evaluate the impact of P-gp-mediated DDI at the rat BBB. We successfully established the IVIVC, which indicated the potential DDI in the presence of potent P-gp inhibitors. On the basis of the IVIVC in rats and K(i) values in human MDR1, we speculated that clinically used P-gp inhibitors do not cause DDI at the human BBB, because none of the compounds studied showed [I(,unbound)/K(i)] values of >1 at therapeutic doses. |
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Authors:
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Hiroshi Sugimoto; Hideki Hirabayashi; Yoshiaki Kimura; Atsutoshi Furuta; Nobuyuki Amano; Toshiya Moriwaki |
Publication Detail:
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Type: Journal Article Date: 2010-10-20 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 39 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 8-14 Citation Subset: IM |
Affiliation:
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Discovery Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. sugimoto_hiroshi1@takeda.co.jp |
Export Citation:
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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