Neuroscience Letters 452 (2009) 12–16 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Interactions between riluzole and ABCG2/BCRP transporter Aline Milane a , Sarah Vautier a , Hélène Chacun c , Vincent Meininger d , Gilbert Bensimon e , Robert Farinotti a,b , Christine Fernandez a,b,∗ a Université Paris-Sud XI, Laboratoire de Barrières et Passage des Médicaments, EA 2706, Faculty of Pharmacy, Chatenay-Malabry, France b Department of Pharmacy, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France c Université Paris-Sud XI, CNRS UMR 8612, Physico-Chimie, Pharmacotechnie and Biopharmacie, Faculty of Pharmacy, Chatenay-Malabry, France d Department of Neurology, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France e Department of Pharmacology, Pitié Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris and Université Pierre et Marie Curie (Paris-VI), Paris, France article info Article history: Received 17 October 2008 Received in revised form 19 December 2008 Accepted 31 December 2008 Keywords: BCRP Riluzole Amyotrophic lateral sclerosis Blood–brain barrier CF1 mdr1a (-/-) mice BeWo cells abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disease. Drugs used in this disease need to cross the blood–brain barrier (BBB). Only riluzole is approved for ALS treatment. We have investigated riluzole as a breast cancer resistance protein (BCRP) substrate by studying its brain transport in CF1 mdr1a (-/-) mice and its intracellular uptake on BeWo cells (human placental choriocarcinoma cell line). We have also investigated the effect of riluzole on BCRP expression level and on its activity using the prazocin as a test probe for brain transport and intracellular uptake. Assays on mdr1a (-/-) mice and BeWo cells showed a higher uptake of riluzole when pretreated with a BCRP inhibitor. After repeated doses of riluzole, BCRP activity was increased in CF1 mdr1a (-/-) mice, riluzole uptake was decrease and both BCRP expression and activity were increased in BeWo cells. In conclusion, we report in this study that riluzole is transported by BCRP at the BBB level and can enhance its function. These results taken with our previous studies on riluzole and P-glycoprotein show that drug–drug interactions between riluzole and efflux transporters substrates may occur at the BBB level and should be taken into account in future clinical trial design in ALS. © 2009 Elsevier Ireland Ltd. All rights reserved. The blood–brain barrier (BBB) maintains the homeostasis of the brain by preventing the entry of toxic and waste products from the blood to the brain. This barrier is formed by a wall of capillary endothelial cells and its tightness is enforced by the tight junctions between the cells and by the astrocytic end feets and pericytes [2]. The presence of efflux transporters on the cell apical membrane contribute to this protection by expelling their substrates out of the brain [25]. In clinical development, CNS-acting drugs have the poorest success rate due especially to the poor permeability of the BBB. The efflux transporters also called efflux pumps belong to the superfamily of ATP Binding Cassette (ABC transporters). This fam- ily includes ABCB1 (P-gp), ABCG2 (BCRP) and ABCC (MRPs) [25]. P-gp is the most studied and is highly expressed in the brain capil- lary system. ABC transporters are usually split into two halves, each with a nucleotide binding domain. At the opposite, BCRP is a half transporter with only one nuclear binding domain and six trans- membrane domains and its function requires homo-dimerization ∗ Corresponding author at: Laboratoire de Barrières et Passage des Médicaments, EA 2706, Tour D1, Faculty of Pharmacy, 5 rue JB Clement, 92296 Chatenay-Malabry, France. Tel.: +33 1 42 16 20 12; fax: +33 1 46 83 56 18. E-mail address: christine.fernandez@psl.aphp.fr (C. Fernandez). or tetramerization. BCRP is one of the latest discovered efflux pumps to be involved in the multi drug resistance (MDR) phe- nomenon and an increasing interest is given to this transporter [16]. BCRP has been localized in various tissues and physiological barriers, including the BBB. Like P-gp, BCRP is highly expressed at the luminal side of the brain endothelium [11,32]. BCRP has sub- sequently been reported to transport numerous molecules such as anticancer agents (mitoxantrone, topotecan, methotrexate), cime- tidine, fluoroquinolone antibiotics, prazocin and tyrosine kinase inhibitors [5,9,16,18,22,25]. Drug–drug interactions (DDI) resulting from modulation of multi-drug resistance proteins may be a clin- ical concern. Therefore, FDA guidelines demand determination of whether a drug candidate is a substrate and/or inhibitor of efflux transporters [10]. Amyotrophic lateral sclerosis (ALS) is a late onset neurode- generative disease characterized by progressive muscle weakness, muscle atrophy and paralysis, usually leading to death within 2–5 years [7,12]. Only one drug, riluzole, has been shown to modify the survival rate in ALS patients. The neuroprotective properties of rilu- zole are due to its anti-glutamatergic effects. However, this drug offers only a modest benefit [4,15]. We have already studied the interactions of riluzole with P-gp at the BBB level and showed that riluzole is transported out of the brain by P-gp [19]. To our knowl- edge, there is no study on the interactions between riluzole and 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2008.12.061