Amantadine, a drug used for the blockage of NMDA receptors, is well-known to exhibit neuroprotective effects. Accordingly, assessment of amantadine transport at retinal barriers could result in the application of amantadine for retinal diseases such as glaucoma. The objective of this study was to elucidate the retinal distribution of amantadine across the inner and outer blood–retinal barrier (BRB). In vivo blood-to-retina [3H]amantadine transport was investigated by using the rat retinal uptake index method, which was significantly reduced by unlabeled amantadine. This result indicated the involvement of carrier-mediated processes in the retinal distribution of amantadine. In addition, in vitro model cells of the inner and outer BRB (TR-iBRB2 and RPE-J cells) exhibited saturable kinetics (Km in TR-iBRB2 cells, 79.4 µM; Km in RPE-J cells, 90.5 and 9830 µM). The inhibition of [3H]amantadine uptake by cationic drugs/compounds indicated a minor contribution of transport systems that accept cationic drugs (e.g., verapamil), as well as solute carrier (SLC) organic cation transporters. Collectively, these outcomes suggest that carrier-mediated transport systems, which differ from reported transporters and mechanisms, play a crucial role in the retinal distribution of amantadine across the inner/outer BRB.
Blood-to-retina transport across the inner blood–retinal barrier (BRB) is a key determinant of retinal drug concentration and pharmacological effect. Recently, we reported on the amantadine-sensitive drug transport system, which is different from well-characterized transporters, at the inner BRB. Since amantadine and its derivatives exhibit neuroprotective effects, it is expected that a detailed understanding of this transport system would lead to the efficient retinal delivery of these potential neuroprotective agents for the treatment of retinal diseases. The objective of this study was to characterize the structural features of compounds for the amantadine-sensitive transport system. Inhibition analysis conducted on a rat inner BRB model cell line indicated that the transport system strongly interacts with lipophilic amines, especially primary amines. In addition, lipophilic primary amines that have polar groups, such as hydroxy and carboxy groups, did not inhibit the amantadine transport system. Furthermore, certain types of primary amines with an adamantane skeleton or linear alkyl chain exhibited a competitive inhibition of amantadine uptake, suggesting that these compounds are potential substrates for the amantadine-sensitive drug transport system at the inner BRB. These results are helpful for producing the appropriate drug design to improve the blood-to-retina delivery of neuroprotective drugs.
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