Minocycline and riluzole brain disposition: interactions with p-glycoprotein at the blood-brain barrier.
Amyotrophic lateral sclerosis is a neurodegenerative fatal disease. The only drug recognized to increase the survival time is riluzole(RLZ). In animal models, minocycline (MNC) delayed the onset of the disease and increased the survival time (in combination with RLZ). The objective of our work was to study the interactions between RLZ, MNC and the efflux pump p-glycoprotein (p-gp) at the blood-brain barrier. We investigated these two drugs as: (i) p-gp substrates by comparing their brain uptake in CF1 mdr1a (-/-) and mdr1a (+/+) mice, (ii) p-gp modulators by studying their effect on the cerebral uptake of digoxin. mdr1a (-/-) mice showed higher brain uptake of MNC and RLZ than mdr1a (+/+) (in a 1.6- and 1.4-fold, respectively); and in mdr1a (+/+) mice pre-treated with repeated doses of MNC, brain uptake of digoxin was increased. When both drugs were administrated to mdr1a (+/+) mice, MNC increased the brain uptake of RLZ in a 2.1-fold. In conclusion, MNC and RLZ are both p-gp substrates. MNC is also a p-gp inhibitor and increases the brain diffusion of RLZ. In vitro experiments with the GPNT cell line confirmed these results. These interactions should be taken into account in the design of future clinical trials.
Milane
Aline
A
Department of Clinical Pharmacy, Barrières et Passage des Médicaments, Faculty of Pharmacy, University of Paris Sud, Chatenay-Malabry, France.
Fernandez
Christine
C
Vautier
Sarah
S
Bensimon
Gilbert
G
Meininger
Vincent
V
Farinotti
Robert
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004077:Digoxin / Q000097:blood / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008911:Minocycline / Q000097:blood / Q000493:pharmacokinetics*; D018696:Neuroprotective Agents / Q000097:blood / Q000493:pharmacokinetics; D019782:Riluzole / Q000097:blood / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018696:Neuroprotective Agents; D004077:Digoxin; D019782:Riluzole; D008911:Minocycline