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J Pharm Sci. 2017 Sep;106(9):2483-2490. doi: 10.1016/j.xphs.2017.04.046. Epub 2017 May 4.

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

Author information

1
Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
2
Department of Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: nakanish@p.kanazawa-u.ac.jp.

Abstract

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 (IC50,2A1 of 0.17 μM), and its IC50 values to MRP4-mediated PGE2 transport (IC50,MRP4) and PGE2 synthesis in human U-937 cells treated with phorbol 12-myristate 13-acetate (IC50,Syn) were 73.6 and 336.7 times higher than IC50,2A1, 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.

KEYWORDS:

drug effects; organic anion-transporting polypeptide transporters; pharmacodynamics; pharmacokinetics; structure-activity relationship (SAR); transport

PMID:
28479361
DOI:
10.1016/j.xphs.2017.04.046
[Indexed for MEDLINE]

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