Interactions between riluzole and ABCG2/BCRP transporter.
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.
Milane
Aline
A
Université Paris-Sud XI, Laboratoire de Barrières et Passage des Médicaments, EA 2706, Faculty of Pharmacy, Chatenay-Malabry, France.
Vautier
Sarah
S
Chacun
Hélène
H
Meininger
Vincent
V
Bensimon
Gilbert
G
Farinotti
Robert
R
Fernandez
Christine
C
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002822:Choriocarcinoma; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019782:Riluzole / Q000378:metabolism* / Q000494:pharmacology; D014162:Transfection / Q000379:methods
C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D019782:Riluzole; C095122:multidrug resistance protein 3; D011224:Prazosin