Minocycline and riluzole brain disposition

Abstract

Amyotrophic lateral sclerosis is a neurodegenerative fataldisease. The only drug recognized to increase the survivaltime is riluzole(RLZ). In animal models, minocycline (MNC)delayed the onset of the disease and increased the survivaltime (in combination with RLZ). The objective of our workwas to study the interactions between RLZ, MNC and theefflux pump p-glycoprotein (p-gp) at the blood–brain barrier.We investigated these two drugs as: (i) p-gp substrates bycomparing their brain uptake in CF1 mdr1a ()/)) and mdr1a(+/+) mice, (ii) p-gp modulators by studying their effect onthe cerebral uptake of digoxin. mdr1a ()/) ) mice showedhigher brain uptake of MNC and RLZ than mdr1a (+/+) (in a1.6- and 1.4-fold, respectively); and in mdr1a (+/+) micepre-treated with repeated doses of MNC, brain uptake ofdigoxin was increased. When both drugs were administratedto mdr1a (+/+) mice, MNC increased the brain uptake ofRLZ in a 2.1-fold. In conclusion, MNC and RLZ are bothp-gp substrates. MNC is also a p-gp inhibitor and increasesthe brain diffusion of RLZ. In vitro experiments with theGPNT cell line confirmed these results. These interactionsshould be taken into account in the design of future clinicaltrials.