Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1
Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:106 |
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| Enthalten in: |
Journal of pharmaceutical sciences - 106(2017), 9 vom: 15. Sept., Seite 2483-2490 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kamo, Shunsuke [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 30.04.2018 Date Revised 13.11.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.xphs.2017.04.046 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM271647264 |
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| 520 | |a Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Tamai, Ikumi |e verfasserin |4 aut | |
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