These results indicate favorable intraocular penetration characteristics of ripasudil following topical administration.

Naturally occurring prostaglandin E 2 (PGE 2 ) plays a role in inflammatory responses through eicosanoid signaling pathways. PGE 2 is impermeable to cell membranes at physiological pH and needs solute carrier across the membranes; however, it remains unclear how intercellular concentrations of PGE 2 are regulated under the condition of inflammation. We aimed to clarify a role of organic anion-transporting polypeptide 2A1 (OATP2A1/SLCO2A1), also known as prostaglandin transporter (PGT), in PGE 2 release from cells. Human bronchial epithelial BEAS-2B cells were treated with lipopolysaccharide (LPS), and PGT inhibitors were tested to evaluate contribution of PGT to PGE 2 release by assessing its extracellular concentration and characterizing PGT-mediated PGE 2 efflux in Xenopus laevis oocytes. As a result, LPS elevated mRNA expression of a pro-inflammatory cytokine IL6 and extracellular concentration of PGE 2 in human bronchial epithelial BEAS-2B cells. PGT inhibitors tested (e.g. bromocresol green (BCG), bromosulfophthalein (BSP), and PGB 1 ) significantly inhibited efflux of PGE 2 from oocytes expressing PGT. Similarly, the amount of released PGE 2 from the BEAS-2B cells decreased in the presence of BCG and BSP by 45 and 44% respectively while TGBz increased the concentration by 71%, suggesting that PGT mediates the release. In conclusion, these results imply a role of PGT in regulating intra-and extracellular concentrations of PGE 2 in response to cells under inflammatory conditions.

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