Acamprosate is an inhibitor of the renal organic anion transporter (OAT) 1

Irina-Elena Antonescu (Member of author group), Maria Karlgren (Member of author group), Maria Pedersen, Ivailo Simoff (Member of author group), Christel Bergström (Member of author group), Sibylle Neuhoff (Member of author group), Per Artursson (Member of author group), Bente Steffansen (Member of author group), Carsten Uhd Nielsen (Member of author group)

Research output: Contribution to conference without publisher/journalConference abstract for conferenceCommunication

Abstract

Introduction. Acamprosate is a BCS class III, non-metabolized, anionic drug substance for which the excretion mechanism is not fully understood. Intravenous administration in rats of acamprosate together with probenecid, a known substrate and inhibitor of the organic anion transporter (OAT) 1 (SLC22A6) (1), decreased the renal clearance (ClR) of acamprosate in a dose-dependent manner (2). The hypothesis of the present study was that renal OATs expressed in the basolateral membrane of the proximal tubule epithelium (3) could be the carrier contributing to renal excretion of acamprosate and the reason for potential acamprosate-drug (e.g. probenecid) interactions.
Aim. To investigate if acamprosate interacts with OAT1 by measuring the concentration-dependent effect of acamprosate on the uptake of [14C]-p-aminohippuric acid ([14C]-PAH), a well-established substrate of OAT1 (4).
Method. The apical uptake of 0.5 μCi/mL [14C]-PAH was measured for 5 minutes at 37°C and 100 rpm in the presence of 0 – 33 000 μM acamprosate in human embryonic kidney (HEK)293 cells transiently expressing OAT1 (Corning TransportoCells OAT1), or in a HEK293-Flp-in cell line stably expressing OAT1 (developed in-house). The uptake was in both series measured in parallel in mock-transfected HEK293 cells grown under similar cell culture conditions.
Results. A significant, time-dependent and saturable increase of [14C]-PAH apical uptake was observed in the OAT1-transfected HEK293 cells compared to mock-transfected cells. The apical uptake of [14C]-PAH in OAT1-transfected cells was decreased in the presence of acamprosate in a concentration-dependent manner, while no effect of acamprosate was observed in the mock-transfected cells. The mean (+/- SD) inhibition constant for [14C]-PAH uptake (IC50) was 1 042 ± 134 and 902 ± 20 μM in the transiently (n=3) and stably transfected (N=3, n=2) HEK293-OAT1 cells, respectively.
Conclusion. Acamprosate inhibits OAT1 in vitro at concentrations close to the maximum unbound plasma concentration of acamprosate, cmax = 154-768 μM (5), obtained after intravenous administration [333-2130 mg].
References
1. Nigam SK, Bush KT, Martovetsky G, Ahn SY, Liu HC, Richard E, et al. The organic anion transporter (OAT) family: a systems biology perspective. Physiol Rev. 2015;95(1):83-123.
2. Zornoza T, Guerri C, Polache A, Granero L. Disposition of acamprosate in the rat: influence of probenecid. Biopharm Drug Dispos. 2002;23(7):283-91.
3. Wright SH, Dantzler WH. Molecular and cellular physiology of renal organic cation and anion transport. Physiol Rev. 2004;84(3):987-1049.
4. FDA. In Vitro Metabolism and Transporter-Mediated Drug-Drug Interaction Studies - Guidance for Industry. In: CDER, editor. Silver Spring, MD: U.S. Department of Health and Human Services; 2017. p. 1-37.
5. Approval package for application number 21-431: Campral clinical pharmacology and biopharmaceutics review: Center for drug evaluation and research; 2004 [cited 2018 08 13]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-431_Campral_BioPharmr.pdf.
Original languageEnglish
Publication date14. Jan 2019
Publication statusPublished - 14. Jan 2019
EventNordic POP 1st Annual Meeting - Holmenkollen, Oslo, Norway
Duration: 14. Jan 201916. Jan 2019

Conference

ConferenceNordic POP 1st Annual Meeting
LocationHolmenkollen
CountryNorway
CityOslo
Period14/01/201916/01/2019

Fingerprint

Kidney
Probenecid
HEK293 Cells
acamprosate
Pharmaceutical Preparations
p-Aminohippuric Acid
Drug Evaluation
Systems Biology
Clinical Pharmacology
Drug Interactions
Silver
Inhibitory Concentration 50
Cations
Epithelium
Cell Line
Membranes

Keywords

  • Acamprosate
  • Excretion mechanism
  • Organic Anion Transporters
  • Transporter inhibition

Cite this

Antonescu, I-E., Karlgren, M., Pedersen, M., Simoff, I., Bergström, C., Neuhoff, S., ... Nielsen, C. U. (2019). Acamprosate is an inhibitor of the renal organic anion transporter (OAT) 1. Abstract from Nordic POP 1st Annual Meeting, Oslo, Norway.
Antonescu, Irina-Elena ; Karlgren, Maria ; Pedersen, Maria ; Simoff, Ivailo ; Bergström, Christel ; Neuhoff, Sibylle ; Artursson, Per ; Steffansen, Bente ; Nielsen, Carsten Uhd. / Acamprosate is an inhibitor of the renal organic anion transporter (OAT) 1. Abstract from Nordic POP 1st Annual Meeting, Oslo, Norway.
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Antonescu, I-E, Karlgren, M, Pedersen, M, Simoff, I, Bergström, C, Neuhoff, S, Artursson, P, Steffansen, B & Nielsen, CU 2019, 'Acamprosate is an inhibitor of the renal organic anion transporter (OAT) 1', Nordic POP 1st Annual Meeting, Oslo, Norway, 14/01/2019 - 16/01/2019.

Acamprosate is an inhibitor of the renal organic anion transporter (OAT) 1. / Antonescu, Irina-Elena (Member of author group); Karlgren, Maria (Member of author group); Pedersen, Maria; Simoff, Ivailo (Member of author group); Bergström, Christel (Member of author group); Neuhoff, Sibylle (Member of author group); Artursson, Per (Member of author group); Steffansen, Bente (Member of author group); Nielsen, Carsten Uhd (Member of author group).

2019. Abstract from Nordic POP 1st Annual Meeting, Oslo, Norway.

Research output: Contribution to conference without publisher/journalConference abstract for conferenceCommunication

TY - ABST

T1 - Acamprosate is an inhibitor of the renal organic anion transporter (OAT) 1

AU - Pedersen, Maria

A2 - Antonescu, Irina-Elena

A2 - Karlgren, Maria

A2 - Simoff, Ivailo

A2 - Bergström, Christel

A2 - Neuhoff, Sibylle

A2 - Artursson, Per

A2 - Steffansen, Bente

A2 - Nielsen, Carsten Uhd

PY - 2019/1/14

Y1 - 2019/1/14

N2 - Introduction. Acamprosate is a BCS class III, non-metabolized, anionic drug substance for which the excretion mechanism is not fully understood. Intravenous administration in rats of acamprosate together with probenecid, a known substrate and inhibitor of the organic anion transporter (OAT) 1 (SLC22A6) (1), decreased the renal clearance (ClR) of acamprosate in a dose-dependent manner (2). The hypothesis of the present study was that renal OATs expressed in the basolateral membrane of the proximal tubule epithelium (3) could be the carrier contributing to renal excretion of acamprosate and the reason for potential acamprosate-drug (e.g. probenecid) interactions.Aim. To investigate if acamprosate interacts with OAT1 by measuring the concentration-dependent effect of acamprosate on the uptake of [14C]-p-aminohippuric acid ([14C]-PAH), a well-established substrate of OAT1 (4).Method. The apical uptake of 0.5 μCi/mL [14C]-PAH was measured for 5 minutes at 37°C and 100 rpm in the presence of 0 – 33 000 μM acamprosate in human embryonic kidney (HEK)293 cells transiently expressing OAT1 (Corning TransportoCells OAT1), or in a HEK293-Flp-in cell line stably expressing OAT1 (developed in-house). The uptake was in both series measured in parallel in mock-transfected HEK293 cells grown under similar cell culture conditions.Results. A significant, time-dependent and saturable increase of [14C]-PAH apical uptake was observed in the OAT1-transfected HEK293 cells compared to mock-transfected cells. The apical uptake of [14C]-PAH in OAT1-transfected cells was decreased in the presence of acamprosate in a concentration-dependent manner, while no effect of acamprosate was observed in the mock-transfected cells. The mean (+/- SD) inhibition constant for [14C]-PAH uptake (IC50) was 1 042 ± 134 and 902 ± 20 μM in the transiently (n=3) and stably transfected (N=3, n=2) HEK293-OAT1 cells, respectively.Conclusion. Acamprosate inhibits OAT1 in vitro at concentrations close to the maximum unbound plasma concentration of acamprosate, cmax = 154-768 μM (5), obtained after intravenous administration [333-2130 mg].References1. Nigam SK, Bush KT, Martovetsky G, Ahn SY, Liu HC, Richard E, et al. The organic anion transporter (OAT) family: a systems biology perspective. Physiol Rev. 2015;95(1):83-123.2. Zornoza T, Guerri C, Polache A, Granero L. Disposition of acamprosate in the rat: influence of probenecid. Biopharm Drug Dispos. 2002;23(7):283-91.3. Wright SH, Dantzler WH. Molecular and cellular physiology of renal organic cation and anion transport. Physiol Rev. 2004;84(3):987-1049.4. FDA. In Vitro Metabolism and Transporter-Mediated Drug-Drug Interaction Studies - Guidance for Industry. In: CDER, editor. Silver Spring, MD: U.S. Department of Health and Human Services; 2017. p. 1-37.5. Approval package for application number 21-431: Campral clinical pharmacology and biopharmaceutics review: Center for drug evaluation and research; 2004 [cited 2018 08 13]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-431_Campral_BioPharmr.pdf.

AB - Introduction. Acamprosate is a BCS class III, non-metabolized, anionic drug substance for which the excretion mechanism is not fully understood. Intravenous administration in rats of acamprosate together with probenecid, a known substrate and inhibitor of the organic anion transporter (OAT) 1 (SLC22A6) (1), decreased the renal clearance (ClR) of acamprosate in a dose-dependent manner (2). The hypothesis of the present study was that renal OATs expressed in the basolateral membrane of the proximal tubule epithelium (3) could be the carrier contributing to renal excretion of acamprosate and the reason for potential acamprosate-drug (e.g. probenecid) interactions.Aim. To investigate if acamprosate interacts with OAT1 by measuring the concentration-dependent effect of acamprosate on the uptake of [14C]-p-aminohippuric acid ([14C]-PAH), a well-established substrate of OAT1 (4).Method. The apical uptake of 0.5 μCi/mL [14C]-PAH was measured for 5 minutes at 37°C and 100 rpm in the presence of 0 – 33 000 μM acamprosate in human embryonic kidney (HEK)293 cells transiently expressing OAT1 (Corning TransportoCells OAT1), or in a HEK293-Flp-in cell line stably expressing OAT1 (developed in-house). The uptake was in both series measured in parallel in mock-transfected HEK293 cells grown under similar cell culture conditions.Results. A significant, time-dependent and saturable increase of [14C]-PAH apical uptake was observed in the OAT1-transfected HEK293 cells compared to mock-transfected cells. The apical uptake of [14C]-PAH in OAT1-transfected cells was decreased in the presence of acamprosate in a concentration-dependent manner, while no effect of acamprosate was observed in the mock-transfected cells. The mean (+/- SD) inhibition constant for [14C]-PAH uptake (IC50) was 1 042 ± 134 and 902 ± 20 μM in the transiently (n=3) and stably transfected (N=3, n=2) HEK293-OAT1 cells, respectively.Conclusion. Acamprosate inhibits OAT1 in vitro at concentrations close to the maximum unbound plasma concentration of acamprosate, cmax = 154-768 μM (5), obtained after intravenous administration [333-2130 mg].References1. Nigam SK, Bush KT, Martovetsky G, Ahn SY, Liu HC, Richard E, et al. The organic anion transporter (OAT) family: a systems biology perspective. Physiol Rev. 2015;95(1):83-123.2. Zornoza T, Guerri C, Polache A, Granero L. Disposition of acamprosate in the rat: influence of probenecid. Biopharm Drug Dispos. 2002;23(7):283-91.3. Wright SH, Dantzler WH. Molecular and cellular physiology of renal organic cation and anion transport. Physiol Rev. 2004;84(3):987-1049.4. FDA. In Vitro Metabolism and Transporter-Mediated Drug-Drug Interaction Studies - Guidance for Industry. In: CDER, editor. Silver Spring, MD: U.S. Department of Health and Human Services; 2017. p. 1-37.5. Approval package for application number 21-431: Campral clinical pharmacology and biopharmaceutics review: Center for drug evaluation and research; 2004 [cited 2018 08 13]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-431_Campral_BioPharmr.pdf.

KW - Acamprosate

KW - Excretion mechanism

KW - Organic Anion Transporters

KW - Transporter inhibition

M3 - Conference abstract for conference

ER -

Antonescu I-E, Karlgren M, Pedersen M, Simoff I, Bergström C, Neuhoff S et al. Acamprosate is an inhibitor of the renal organic anion transporter (OAT) 1. 2019. Abstract from Nordic POP 1st Annual Meeting, Oslo, Norway.