title: Brain and plasma riluzole pharmacokinetics: effect of minocycline combination.
abstract: OBJECTIVE
  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-infinity increase proportionally with plasmatic AUC0-infinity. At the dose of 10 mg/kg, the cerebral AUC0-infinity /plasmatic AUC0-infinity 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-infinity 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.
authors.affiliation: Laboratoire de Barrières et Passage des Médicaments, EA 2706, Faculty of Pharmacy, Université Paris-Sud XI, Chatenay-Malabry, Chatenay-Malabry, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Milane
authors.forename: Lionel
authors.initials: L
authors.lastname: Tortolano
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bensimon
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000633:toxicity; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008911:Minocycline / Q000494:pharmacology* / Q000633:toxicity; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D020258:Neurotoxicity Syndromes / Q000209:etiology; D019782:Riluzole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000900:Anti-Bacterial Agents; D018696:Neuroprotective Agents; D019782:Riluzole; C095122:multidrug resistance protein 3; D008911:Minocycline