Drug efflux transporter inhibition boosts ALS treatment in mice

By Will Boggs MD

NEW YORK (Reuters Health) - Inhibiting the blood-brain and spinal cord barrier's drug efflux transporters improves the efficacy of ALS treatment with riluzole in a mouse model.

"This is a proof-of-principle study that sheds light into a basic pathological mechanism at play in ALS that negatively affects our ability to deliver drugs efficiently," Dr. Piera Pasinelli from Thomas Jefferson University in Philadelphia told Reuters Health by email. "If the findings hold true in clinical trials, we'll hopefully be able to improve the efficacy of the only FDA approved drug for ALS while better and more potent therapies are being developed."

At least in the mouse ALS model, riluzole brain disposition is limited at the blood-brain and spinal cord barrier through interaction with the drug efflux transporters P-glycoprotein (P-gp) and breast cancer-resistant protein (BRCP), Dr. Pasinelli and colleagues write in Annals of Clinical and Translational Neurology, online November 21.

The team investigated whether inhibition of these transporters with elacridar treatment would improve riluzole central nervous system bioavailability and prolong its therapeutic effects in ALS mice.

Before treatment with elacridar, endothelial cells of the ALS mouse blood-spinal cord barrier had elevated expression of P-gp. Homogenates of lumbar spinal cords of four ALS patients showed similar increases.

Treatment with elacridar did not affect overall expression of P-gp or BRCP, but it did inhibit their function, resulting in a significant increase in riluzole spinal cord concentrations in ALS diseased mice, according to researchers.

Combined treatment with riluzole and elacridar at symptom onset significantly extended survival (by 13%), compared with control/placebo and riluzole/placebo treatment.

Moreover, throughout 40 days of treatment, riluzole/elacridar-treated mice maintained significantly higher compound muscle action potentials compared with the riluzole/placebo-treated mice.

"Drug efflux transporter-mediated pharmacoresistance is a well-characterized phenomenon in other diseases of the nervous system like epilepsy," Dr. Pasinelli said. "Surprisingly it has been an underestimated phenomenon in ALS. While our study has immediate implications for ALS primarily, the approach to combine a therapeutic drug with drug efflux transporter inhibitors is not new, and it is in use for other diseases."

"In particular, our study shows that the effect of P-gp and BCRP on drug penetration needs to be considered specifically in the context of ALS," Dr. Pasinelli said.

"Elacridar has not been approved for chronic use in ALS yet, although it has been approved for clinical trials for other indications," he added.

SOURCE: http://bit.ly/1vQWZF3

Ann Clin Transl Neurol 2014.

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