Brain and plasma riluzole pharmacokinetics
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 bene...
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| مؤلفون آخرون: | , , , , |
| التنسيق: | article |
| منشور في: |
2016
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| الوصول للمادة أونلاين: | http://hdl.handle.net/10725/4496 http://dx.doi.org/10.18433/J36C78 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://ejournals.library.ualberta.ca/index.php/JPPS/article/viewArticle/4596 |
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| _version_ | 1864513463677616128 |
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| author | Milane, Aline |
| author2 | Tortolano, Lionel Fernadez, Christine Bensimon, Gilbert Meininger, Vincent Farinotti, Robert |
| author2_role | author author author author author |
| author_facet | Milane, Aline Tortolano, Lionel Fernadez, Christine Bensimon, Gilbert Meininger, Vincent Farinotti, Robert |
| author_role | author |
| dc.creator.none.fl_str_mv | Milane, Aline Tortolano, Lionel Fernadez, Christine Bensimon, Gilbert Meininger, Vincent Farinotti, Robert |
| dc.date.none.fl_str_mv | 2016-10-04T09:31:23Z 2016-10-04T09:31:23Z 2016-10-04 |
| dc.identifier.none.fl_str_mv | 1482-1826 http://hdl.handle.net/10725/4496 http://dx.doi.org/10.18433/J36C78 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. http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://ejournals.library.ualberta.ca/index.php/JPPS/article/viewArticle/4596 |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Journal of Pharmacy and Pharmaceutical Sciences |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | Brain and plasma riluzole pharmacokinetics effect of minocyline combination |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_f7bff3d9bdbee6b69eb886e6167dfd9a |
| identifier_str_mv | 1482-1826 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. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/4496 |
| publishDate | 2016 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Brain and plasma riluzole pharmacokineticseffect of minocyline combinationMilane, AlineTortolano, LionelFernadez, ChristineBensimon, GilbertMeininger, VincentFarinotti, RobertPurpose. 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.PublishedN/A2016-10-04T09:31:23Z2016-10-04T09:31:23Z2016-10-04Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1482-1826http://hdl.handle.net/10725/4496http://dx.doi.org/10.18433/J36C78Milane, 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.http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.phphttp://ejournals.library.ualberta.ca/index.php/JPPS/article/viewArticle/4596enJournal of Pharmacy and Pharmaceutical Sciencesinfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/44962021-03-19T10:00:50Z |
| spellingShingle | Brain and plasma riluzole pharmacokinetics Milane, Aline |
| status_str | publishedVersion |
| title | Brain and plasma riluzole pharmacokinetics |
| title_full | Brain and plasma riluzole pharmacokinetics |
| title_fullStr | Brain and plasma riluzole pharmacokinetics |
| title_full_unstemmed | Brain and plasma riluzole pharmacokinetics |
| title_short | Brain and plasma riluzole pharmacokinetics |
| title_sort | Brain and plasma riluzole pharmacokinetics |
| url | http://hdl.handle.net/10725/4496 http://dx.doi.org/10.18433/J36C78 http://libraries.lau.edu.lb/research/laur/terms-of-use/articles.php http://ejournals.library.ualberta.ca/index.php/JPPS/article/viewArticle/4596 |