Inhibiting drug efflux transporters improves efficacy of ALS therapeutics.

The limited progress in identifying successful therapies in Amyotrophic Lateral Sclerosis (ALS) has only resulted in one moderately effective pharmacological agent, riluzole.1,2 In research on the SOD1-G93A mouse model of ALS, riluzole showed a modest effect on survival when administrated prior to disease onset.3 Since then, follow-up studies have shown conflicting results,4–6 due to differences in trial design and lack of pharmacokinetic measurements. Riluzole brain disposition is limited in the ALS mouse model through interaction with the drug efflux transporters P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP) at the blood-brain/spinal cord barrier (BBB/BSCB).7,8 Accordingly, riluzole loses effectiveness as disease progresses in this model.9 Similarly, in patients with ALS, riluzole loses effectiveness in the later stages of disease.10 Studies in patients demonstrated that riluzole is particularly effective in the first 12 months of treatment, reducing mortality by 38% and that this initial efficacy is reduced to 19.4% at 21 months of treatment.11 The negligible therapeutic effect of riluzole in the ALS mice and its modest effect in patients could derive from acquired pharmacoresistance. In previous studies, we reported an ALS-specific and disease-driven increase in expression and function of two drug efflux transporters, P-gp and BCRP, in both ALS mouse spinal cord capillaries and in spinal cord tissue of ALS patients.12 The findings suggested that this increased expression potentially conferred an acquired pharmacoresistance, which could limit the bioavailability of ALS/CNS-targeted therapeutics.12,13 Here, we tested this hypothesis and determined whether improving riluzole CNS bioavailability through inhibition of P-gp and BCRP efflux transporter(s) improves and prolongs riluzole's therapeutic effect(s) in the ALS mice. Given that our ultimate goal is to translate this concept of inhibiting drug efflux to ALS patients' therapy, we further analyzed expression levels of P-gp in human ALS cases.