Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1

To understand interaction of drugs with the prostaglandin transporter OATP2A1/SLCO2A1 that regulates disposition of prostaglandins, we explored the impact of 636 drugs in an FDA-approved drug library on 6-carboxyfluorescein (6-CF) uptake by OATP2A1-expressing HEK293 cells (HEK/2A1). Fifty-one and 10 drugs were found to inhibit and enhance 6-CF uptake by more than 50%, respectively. Effect of the 51 drugs on 6-CF uptake was positively correlated with that on PGE₂ uptake (r = 0.64, p < 0.001). Among those, 5 drugs not structurally related to prostaglandins, suramin, pranlukast, zafirlukast, olmesartan medoxomil, and losartan potassium, exhibited more than 90% PGE₂ uptake inhibition. Inhibitory affinity of suramin to OATP2A1 was the highest (IC_50,2A1 of 0.17 μM), and its IC₅₀ values to MRP4-mediated PGE₂ transport (IC_50,MRP4) and PGE₂ synthesis in human U-937 cells treated with phorbol 12-myristate 13-acetate (IC_50,Syn) were 73.6 and 336.7 times higher than IC_50,2A1, respectively. Moreover, structure-activity relationship study in 29 nonsteroidal anti-inflammatory drugs contained in the library displayed inhibitory activities of anthranilic acid derivatives, but enhancing effects of propionic acid derivatives. These results demonstrate that suramin is a potent selective inhibitor of OATP2A1, providing a comprehensive information about drugs in clinical use that interact with OATP2A1.