facilitate the delivery of folate from the cytoplasm into the retina, thus completing the transcellular transfer. Since the folate receptor a-mediated entry into cells results in the delivery of folates into endosomes, an additional step is needed to deliver folates from the endosomes into cytoplasm. PCFT is a candidate responsible for this process (Qiu et al. 2006). Since there exists an H+ gradient across the endosomal membrane in the endosome-to-cytoplasm direction, folate will get transferred into the cytoplasm via PCFT. PCFT is indeed expressed in RPE cells (Umapathy et al. 2007). Electron microscopic analysis shows that folate receptor a and PCFT colocalize in Müller cells on the endosomal membrane as well as on the plasma membrane (Bozard et al. 2010). Thus, it is conceivable that PCFT colocalizes with folate receptor a in the basolateral membrane of RPE cells and that the two proteins work together in the delivery of folates from choroidal circulation into RPE cells. Folate analogs that serve as antifolates (e.g., methotrexate, pemetrexed) can be delivered into neural retina across the BRB via the concerted actions of the three folate transport proteins. RFC1 transports methotrexate, an antifolate, used in eyes with primary CNS lymphoma, uveitis, and proliferative diabetic retinopathy (Hardwig et al. 2008). However, it would be necessary to consider that the retinal transport of folate analogs via the folate transport proteins may interfere with the entry of the physiologic substrate MTF into retina.

4.2.5  Organic Cationic Drugs

A variety of organic cation transporters (OCTs and OCTNs) accept endogenous and exogenous organic cations as substrates (Koepsell et al. 2007). RVEC express OCTN2 (SLC22A5) (Tachikawa et al. 2010) and RPE cells express OCT3 (SLC22A3) (Rajan et al. 2000). OCTN2 at the inner BRB mediates the blood- to-retina transport of acetyl-L-carnitine (Tachikawa et al. 2010). Acetyl-L- carnitine is effective in improving visual function in patients with early age-related macular degeneration. The Michaelis constant for the transport of acetyl-L- carnitine via OCTN2 in TR-iBRB cells is ~30 mM, a value similar to the physiological levels of these compounds in plasma (carnitine, ~50 mM; acetylcarnitine, ~20 mM) (Tachikawa et al. 2010). Exogenous administration of acetyl-L- carnitine via a systemic route would therefore be able to increase the retinal levels of acetyl-L-carnitine through OCTN2-mediated transport at the inner BRB. Several other cationic and zwitterionic drugs including b-lactam antibiotics such as cephaloridine (Ganapathy et al. 2000), tetraethylammonium, pyrilamine, quinidine, verapamil, and valproate (Ohashi et al. 1999) are transportable substrates for OCTN2. Although the localization of OCT3 in RPE cells remains unknown, its substrates of pharmacological significance include prazocin (a-adrenoceptor antagonist), clonidine (a-adrenoceptor agonist), cimetidine (histamine H1 receptor antagonist), verapamil (calcium channel blocker), imipramine and desipramine (antidepressants), quinine (antimalarial drug), and nicotine and methylenedioxymethamphetamine (an addictive drug) (Koepsell et al.