Brain and Plasma Riluzole Pharmacokinetics: Effect of Minocycline Combination

Aline Milane1, Lionel Tortolano1, Christine Fernandez2, Gilbert Bensimon3, Vincent Meininger4, Robert Farinotti2

1Université Paris-Sud XI, Laboratoire de Barrières et Passage des Médicaments, Chatenay-Malabry, France
2Université Paris-Sud XI, Chatenay-Malabry; Pitié Salpêtrière Hospital, Paris, France
3Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris and Université Pierre et Marie Curie (Paris-VI), Paris, France
4Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France


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 blood-brain barrier level. METHODS: in this work, we studied in CF1 mice, the plasmatic and cerebral pharmacokinetics of riluzole combined or not with minocycline. RESULTS: our results showed that the kinetics of riluzole are not linear with dose, but that cerebral AUC0-∞ increase proportionally with plasmatic AUC0-∞. At the dose of 10 mg/kg, the cerebral AUC0-∞ /plasmatic AUC0-∞ 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 cerebral AUC0-∞ 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 cerebral concentrations could be predicted by plasmatic concentrations. Furthermore, the combination of high doses of minocycline with riluzole could induce neurological toxicity that lead to deceiving results in ALS clinical studies.

J Pharm Pharm Sci, 12 (2): 209-217, 2009

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