Comprehensive Evidence of Carrier-Mediated Distribution of Amantadine to the Retina across the Blood–Retinal Barrier in Rats

Abstract

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.

Aryl hydrocarbon receptor dependent anti-inflammation and neuroprotective effects of tryptophan metabolites on retinal ischemia/reperfusion injury

“…The 2-year phase 3 clinical trial of over 2,000 patients with open-angle glaucoma showed no effects to prevent glaucomatous progression by daily treatment with memantine [ 43 ]. Crossing the BRB is an important factor affecting the efficacy of glaucoma drugs [ 44 , 45 ]. Notably, various tryptophan metabolites have been demonstrated to be able to effectively cross through the blood-brain barrier (BBB) to confer their immunomodulatory effects in CNS [ 10 , 46 ].…”

The Structural Characteristics of Compounds Interacting with the Amantadine-Sensitive Drug Transport System at the Inner Blood–Retinal Barrier

“…Under physiological conditions, amantadine exists mostly in the cationic form [ 24 ]. In addition, our previous results indicated that the amantadine transport system is sensitive to cationic compounds [ 5 ]. The present inhibition study ( Figure 2 and Table 1 ) also showed that several cationic adamantane derivatives that have an amino group on the adamantane skeleton (compounds 1 – 3 and 8 ) inhibited [ 3 H]amantadine uptake by TR-iBRB2 cells.…”

“…Thus, compounds 14 (cycloaliphatic amine) and 23 (linear aliphatic amine), but not compound 3 , were used. The IC 50 values of compounds 9 , 14 , and 23 for amantadine uptake were calculated to be 22.6, 67.0, and 55.3 µM, respectively ( Figure 3 and Table 2 ), and these values were smaller than the K m value (70.9 µM) of amantadine [ 5 ]. This result suggests that these compounds interact with the amantadine transport system with higher affinity than amantadine.…”

“…At the inner BRB, we recently reported that a carrier-mediated transport system contributes to the retinal transport of the cationic compound amantadine, an adamantane derivative, from the blood [ 5 ]. This amantadine transport system is different from typical cation transporters, such as the neutral and basic amino acid transporter (ATB 0,+ /Slc6a14), organic cation transporters 1-2 (OCT1-2/slc22a1-2), multidrug and toxin extrusion protein 1 (MATE1/Slc47a1), carnitine/organic cation transporters 1-2 (OCTN1-2/slc22a4-5), and plasma membrane monoamine transporter (PMAT/slc29a4).…”

“…This amantadine transport system is different from typical cation transporters, such as the neutral and basic amino acid transporter (ATB 0,+ /Slc6a14), organic cation transporters 1-2 (OCT1-2/slc22a1-2), multidrug and toxin extrusion protein 1 (MATE1/Slc47a1), carnitine/organic cation transporters 1-2 (OCTN1-2/slc22a4-5), and plasma membrane monoamine transporter (PMAT/slc29a4). Moreover, based on the analysis of kinetic inhibition, pH-dependence, and L-carnitine sensitivity, the amantadine transport system is likely to be different from other putative cation transport systems of the inner BRB, which transport verapamil, clonidine, and propranolol [ 3 , 4 , 5 ]. Adamantane derivatives, such as amantadine and memantine, are known to exert neuroprotective effects by inhibiting N-methyl-D-aspartate (NMDA) receptors [ 6 , 7 , 8 , 9 ] and are used for the treatment of neurodegenerative disorders of the brain [ 10 , 11 , 12 , 13 ].…”