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

Molecular Pharmaceutics
Sander A A KooijmansJoseph A Nicolazzo

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 depolarizat...Continue Reading

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Citations

Jun 30, 2012·Pharmaceutical Research·Christel A S BergströmJoseph A Nicolazzo
Mar 28, 2013·Fluids and Barriers of the CNS·Babette WekslerPierre-Olivier Couraud
Jun 18, 2016·Journal of Pharmaceutical Sciences·Liang JinJoseph A Nicolazzo
May 6, 2016·Biopharmaceutics & Drug Disposition·Toyofumi SuzukiKazuo Tomono
Oct 9, 2013·Molecular Pharmaceutics·Dharmini C MehtaJoseph A Nicolazzo
Apr 12, 2019·Biomolecules & Therapeutics·Asmita GyawaliYoung-Sook Kang
Feb 2, 2013·The Oncologist·Leslie S KersunKathleen E Sullivan
Dec 20, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anne T NiesMatthias Schwab

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