Memantine transport across the mouse blood-brain barrier is mediated by a cationic influx H+ antiporter.

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Mehta DC, Short JL, Nicolazzo JA

Memantine transport across the mouse blood-brain barrier is mediated by a cationic influx H+ antiporter.

Mol Pharm. 2013 Dec 2;10(12):4491-8. doi: 10.1021/mp400316e. Epub 2013 Oct 29.

PubMed ID

24098999 [ View in PubMed

]

Abstract

Memantine (MEM) is prescribed in mono and combination therapies for treating the symptoms of moderate to severe Alzheimer's disease (AD). Despite MEM being widely prescribed with other AD and non-AD medicines, very little is known about its mechanism of transport across the blood-brain barrier (BBB), and whether the nature of this transport lends MEM to a potential for drug-drug interactions at the BBB. Therefore, the purpose of this study was to characterize the mechanisms facilitating MEM brain uptake in Swiss Outbred mice using an in situ transcardiac perfusion technique, and identify the putative transporter involved in MEM disposition into the brain. Following transcardiac perfusion of MEM with increasing concentrations, the brain uptake of MEM was observed to be saturable. Furthermore, MEM brain uptake was reduced (up to 55%) by various cationic transporter inhibitors (amantadine, quinine, tetraethylammonium, choline and carnitine) and was dependent on extracellular pH, while being independent of membrane depolarization and the presence of Na(+) in the perfusate. In addition, MEM brain uptake was observed to be sensitive to changes in intracellular pH, hence, likely to be driven by H(+)/MEM antiport mechanisms. Taken together, these findings implicate the involvement of an organic cation transporter regulated by proton antiport mechanisms in the transport of MEM across the mouse BBB, possibly the organic cation/carnitine transporter, OCTN1. These studies also clearly demonstrate the brain uptake of MEM is significantly reduced by other cationic compounds, highlighting the need to consider the possibility of drug interactions with MEM at the BBB, potentially leading to reduced brain uptake and, therefore, altered efficacy of MEM when used in patients on multidrug regimens.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Memantine	Sodium/hydrogen exchanger 1	Protein	Humans	Unknown	Not Available	Details
Memantine	Solute carrier family 22 member 4	Protein	Humans	Unknown	Not Available	Details