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

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Antonescu, Irina E.Univ Southern Denmark, Dept Phys Chem & Pharm, Campusvej 55, DK-5230 Odense, Denmark. (author)

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

Article/chapterEnglish2020

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2020-04-24
MDPI,2020
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-413904
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-413904URI
https://doi.org/10.3390/pharmaceutics12040390DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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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 SLC22A6) and OAT3 (gene product of SLC22A8) 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 SLC22A6 or SLC22A8. 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 p-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-m-value of approximately 700 mu M. Probenecid inhibited OAT1-mediated acamprosate uptake with a K-i-value of approximately 13 mu M, which may translate into an estimated clinically significant DDI index. In conclusion, acamprosate was identified as a substrate of OAT1 but not OAT3.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinsk bioteknologi Medicinsk bioteknologi hsv//swe
MEDICAL AND HEALTH SCIENCES Medical Biotechnology Medical Biotechnology hsv//eng
acamprosate
probenecid
organic anion transporter
OAT1
OAT3
HEK293 cells
renal carrier
secretion
drug-drug interaction

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Karlgren, MariaUppsala universitet,Institutionen för farmaci(Swepub:uu)marka263 (author)
Pedersen, Maria L.Univ Southern Denmark, Dept Phys Chem & Pharm, Campusvej 55, DK-5230 Odense, Denmark. (author)
Simoff, IvailoUppsala universitet,Institutionen för farmaci,Drug Optimization and Pharmaceutical Profiling Platform(Swepub:uu)ivasi192 (author)
Bergström, Christel,1973-Uppsala universitet,Institutionen för farmaci(Swepub:uu)cjo29958 (author)
Neuhoff, SibylleCertara UK Ltd, Simcyp Div, Level 2 Acero,1 Concourse Way, Sheffield S1 2BJ, S Yorkshire, England. (author)
Artursson, PerUppsala universitet,Institutionen för farmaci,Drug Optimization and Pharmaceutical Profiling Platform(Swepub:uu)perartur (author)
Steffansen, BenteLEO Pharma, Ind Pk 55, DK-2750 Ballerup, Denmark. (author)
Nielsen, Carsten UhdUniv Southern Denmark, Dept Phys Chem & Pharm, Campusvej 55, DK-5230 Odense, Denmark. (author)
Univ Southern Denmark, Dept Phys Chem & Pharm, Campusvej 55, DK-5230 Odense, Denmark.Institutionen för farmaci (creator_code:org_t)

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In:Pharmaceutics: MDPI12:41999-4923

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