Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions
Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in the kid...
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MDPI AG
2020-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/4/390 |
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| author | Irina E. Antonescu Maria Karlgren Maria L. Pedersen Ivailo Simoff Christel A. S. Bergström Sibylle Neuhoff Per Artursson Bente Steffansen Carsten Uhd Nielsen |
| author_facet | Irina E. Antonescu Maria Karlgren Maria L. Pedersen Ivailo Simoff Christel A. S. Bergström Sibylle Neuhoff Per Artursson Bente Steffansen Carsten Uhd Nielsen |
| author_sort | Irina E. Antonescu |
| collection | DOAJ |
| description | Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in the kidneys, despite the fact that studies have shown renal secretion of acamprosate. The hypothesis of the present study was therefore that renal organic anion transporters (OATs) facilitate the renal excretion of acamprosate in humans. The aim of the present study was to establish and apply OAT1 (gene product of <i>SLC22A6</i>) and OAT3 (gene product of <i>SLC22A8</i>) expressing cell lines to investigate whether acamprosate is a substrate or inhibitor of OAT1 and/or OAT3. The studies were performed in HEK293-Flp-In cells stably transfected with <i>SLC22A6</i> or <i>SLC22A8</i>. Protein and functional data showed that the established cell lines are useful for studying OAT1- and OAT3-mediated transport in bi-laboratory studies. Acamprosate inhibited OAT1-mediated <i>p</i>-aminohippuric acid (PAH) uptake but did not inhibit substrate uptake via OAT3 expressing cells, neither when applied concomitantly nor after a 3 h preincubation with acamprosate. The uptake of PAH via OAT1 was inhibited in a competitive manner by acamprosate and cellular uptake studies showed that acamprosate is a substrate for OAT1 with a K<sub>m</sub>-value of approximately 700 µM. Probenecid inhibited OAT1-mediated acamprosate uptake with a K<sub>i</sub>-value of approximately 13 µM, which may translate into an estimated clinically significant DDI index. In conclusion, acamprosate was identified as a substrate of OAT1 but not OAT3. |
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| id | doaj.art-98594dfdbdd9410b820f985d165d6cfa |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T20:15:39Z |
| publishDate | 2020-04-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-98594dfdbdd9410b820f985d165d6cfa2023-11-19T22:35:17ZengMDPI AGPharmaceutics1999-49232020-04-0112439010.3390/pharmaceutics12040390Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug InteractionsIrina E. Antonescu0Maria Karlgren1Maria L. Pedersen2Ivailo Simoff3Christel A. S. Bergström4Sibylle Neuhoff5Per Artursson6Bente Steffansen7Carsten Uhd Nielsen8Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, DenmarkDepartment of Pharmacy, Uppsala University, Husargatan 3 BMC, SE-751 23 Uppsala, SwedenDepartment of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, DenmarkUppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Department of Pharmacy, Uppsala University, Husargatan 3 BMC, SE-751 23 Uppsala, SwedenDepartment of Pharmacy, Uppsala University, Husargatan 3 BMC, SE-751 23 Uppsala, SwedenCertara UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield S1 2BJ, UKDepartment of Pharmacy, Uppsala University, Husargatan 3 BMC, SE-751 23 Uppsala, SwedenLEO Pharma, Industriparken 55, 2750 Ballerup, DenmarkDepartment of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, DenmarkAcamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in the kidneys, despite the fact that studies have shown renal secretion of acamprosate. The hypothesis of the present study was therefore that renal organic anion transporters (OATs) facilitate the renal excretion of acamprosate in humans. The aim of the present study was to establish and apply OAT1 (gene product of <i>SLC22A6</i>) and OAT3 (gene product of <i>SLC22A8</i>) expressing cell lines to investigate whether acamprosate is a substrate or inhibitor of OAT1 and/or OAT3. The studies were performed in HEK293-Flp-In cells stably transfected with <i>SLC22A6</i> or <i>SLC22A8</i>. Protein and functional data showed that the established cell lines are useful for studying OAT1- and OAT3-mediated transport in bi-laboratory studies. Acamprosate inhibited OAT1-mediated <i>p</i>-aminohippuric acid (PAH) uptake but did not inhibit substrate uptake via OAT3 expressing cells, neither when applied concomitantly nor after a 3 h preincubation with acamprosate. The uptake of PAH via OAT1 was inhibited in a competitive manner by acamprosate and cellular uptake studies showed that acamprosate is a substrate for OAT1 with a K<sub>m</sub>-value of approximately 700 µM. Probenecid inhibited OAT1-mediated acamprosate uptake with a K<sub>i</sub>-value of approximately 13 µM, which may translate into an estimated clinically significant DDI index. In conclusion, acamprosate was identified as a substrate of OAT1 but not OAT3.https://www.mdpi.com/1999-4923/12/4/390acamprosateprobenecidorganic anion transporterOAT1OAT3HEK293 cells |
| spellingShingle | Irina E. Antonescu Maria Karlgren Maria L. Pedersen Ivailo Simoff Christel A. S. Bergström Sibylle Neuhoff Per Artursson Bente Steffansen Carsten Uhd Nielsen Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions Pharmaceutics acamprosate probenecid organic anion transporter OAT1 OAT3 HEK293 cells |
| title | Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions |
| title_full | Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions |
| title_fullStr | Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions |
| title_full_unstemmed | Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions |
| title_short | Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions |
| title_sort | acamprosate is a substrate of the human organic anion transporter oat 1 without oat3 inhibitory properties implications for renal acamprosate secretion and drug drug interactions |
| topic | acamprosate probenecid organic anion transporter OAT1 OAT3 HEK293 cells |
| url | https://www.mdpi.com/1999-4923/12/4/390 |
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