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The involvement of a Na⁺- and Cl⁻-dependent transporter in the brain uptake of amantadine and rimantadine

Kooijmans, Sander A. A.; Senyschyn, Danielle; Mezhiselvam, Muguntha M.; Morizzi, Julia; Charman, Susan A.; Weksler, Babette; Romero, Ignacio-Andres; Couraud, Pierre-Olivier and Nicolazzo, Joseph A. (2012). The involvement of a Na⁺- and Cl⁻-dependent transporter in the brain uptake of amantadine and rimantadine. Molecular pharmaceutics, 9(4) pp. 883–93.

DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1021/mp2004127
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Abstract

Despite their structural similarity, the two anti-influenza adamantane compounds amantadine (AMA) and rimantadine (RIM) exhibit strikingly different rates of blood-brain barrier (BBB) transport. However, the molecular mechanisms facilitating the higher rate of in situ BBB transport of RIM, relative to AMA, remain unclear. The aim of this study, therefore, was to determine whether differences in the extent of brain uptake between these two adamantanes also occurred in vivo, and elucidate the potential carrier protein facilitating their BBB transport using immortalized human brain endothelial cells (hCMEC/D3). Following oral administration to Swiss Outbred mice, RIM exhibited 2.4-3.0-fold higher brain-to-plasma exposure compared to AMA, which was not attributable to differences in the degree of plasma protein binding. At concentrations representative of those obtained in vivo, the hCMEC/D3 cell uptake of RIM was 4.5-15.7-fold higher than that of AMA, with Michaelis-Menten constants 6.3 and 238.4 μM, respectively. The hCMEC/D3 cellular uptake of both AMA and RIM was inhibited by various cationic transporter inhibitors (cimetidine, choline, quinine, and tetraethylammonium) and was dependent on extracellular pH, membrane depolarization and Na⁺ and Cl⁻ ions. Such findings indicated the involvement of the neutral and cationic amino acid transporter B⁰,⁺ (ATB⁰,⁺) in the uptake of AMA and RIM, which was demonstrated to be expressed (at the protein level) in the hCMEC/D3 cells. Indeed, AMA and RIM appeared to interact with this transporter, as shown by a 53-70% reduction in the hCMEC/D3 uptake of the specific ATB⁰,⁺ substrate ³H-glycine in their presence. These studies suggest the involvement of ATB⁰,⁺ in the disposition of these cationic drugs across the BBB, a transporter with the potential to be exploited for targeted drug delivery to the brain.

Item Type: Journal Article
Copyright Holders: 2012 American Chemical Society
ISSN: 1543-8392
Keywords: amantadine; amino acid transporter B0,+; blood−brain barrier; rimantadine
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Related URLs:
Item ID: 34225
Depositing User: Ignacio A Romero
Date Deposited: 23 Aug 2012 08:42
Last Modified: 07 Mar 2014 15:06
URI: http://oro.open.ac.uk/id/eprint/34225
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