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Brain and plasma riluzole pharmacokinetics

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dc.contributor.author Milane, Aline
dc.contributor.author Tortolano, Lionel
dc.contributor.author Fernadez, Christine
dc.contributor.author Bensimon, Gilbert
dc.contributor.author Meininger, Vincent
dc.contributor.author Farinotti, Robert
dc.date.accessioned 2016-10-04T09:31:23Z
dc.date.available 2016-10-04T09:31:23Z
dc.identifier.issn 1482-1826 en_US
dc.identifier.uri http://hdl.handle.net/10725/4496
dc.description.abstract Purpose. Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by the loss of motorneurons. The only drug approved is riluzole. Minocycline is an antibiotic with numerous neuroprotective properties. riluzole and minocycline were given to an animal model of ALS and had beneficial effect on the disease. The combination was then tested in humans in phase II and phase III studies with less beneficial effects and a faster decline of the disease in the group treated with minocycline. In a previous study, we showed that riluzole is transported out of the brain by the P-glycoprotein at the bloodbrain barrier level. In this work, we tested the hypothesis of a drug-drug interaction between riluzole and minocycline. Methods. We studied in CF1 mice, the plasma and brain pharmacokinetics of riluzole combined or not with minocycline. Results. Our results showed that riluzole pharmacokinetics are not linear with dose, but that brain AUC0-t increase proportionally with plasma AUC0-t. At the dose of 10 mg/kg, the brain AUC0-t /plasma AUC0-t ratio was 4.6 in mdr1a (-/-) mice and 2.4 in mdr1a (+/+) mice. The combination of minocycline (170 mg/kg) and riluzole (10 mg/kg) induced a 2 fold increase in the brain AUC0-t of riluzole and induced a neuromuscular toxicity in mice. This effect of minocycline was not found at low concentration (10 mg/kg of minocycline). Conclusions. If our results are confirmed in humans, riluzole brain concentrations could be predicted by plasma concentrations. Furthermore, the combination of high doses of minocycline with riluzole could induce neurological toxicity that lead to deceiving results in ALS clinical studies. Hence, a dose-range of minocycline combined with riluzole should be tested in further clinical studies. en_US
dc.language.iso en en_US
dc.title Brain and plasma riluzole pharmacokinetics en_US
dc.type Article en_US
dc.description.version Published en_US
dc.title.subtitle effect of minocyline combination en_US
dc.author.school SOP en_US
dc.author.idnumber 200904164 en_US
dc.author.department N/A en_US
dc.description.embargo N/A en_US
dc.relation.journal Journal of Pharmacy and Pharmaceutical Sciences en_US
dc.journal.volume 12 en_US
dc.journal.issue 2 en_US
dc.article.pages 209-217 en_US
dc.identifier.doi http://dx.doi.org/10.18433/J36C78 en_US
dc.identifier.ctation Milane, A., Tortolano, L., Fernandez, C., Bensimon, G., Meininger, V., & Farinotti, R. (2009). Brain and plasma riluzole pharmacokinetics: effect of minocycline combination. Journal of Pharmacy & Pharmaceutical Sciences, 12(2), 209-217. en_US
dc.author.email aline.milane@lau.edu.lb en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php en_US
dc.identifier.url http://ejournals.library.ualberta.ca/index.php/JPPS/article/viewArticle/4596 en_US


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