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

Irina-Elena Antonescu (Medlem af forfattergruppering), Maria Karlgren (Medlem af forfattergruppering), Maria Pedersen, Ivailo Simoff (Medlem af forfattergruppering), Christel Bergström (Medlem af forfattergruppering), Sibylle Neuhoff (Medlem af forfattergruppering), Per Artursson (Medlem af forfattergruppering), Bente Steffansen (Medlem af forfattergruppering), Carsten Uhd Nielsen (Medlem af forfattergruppering)

Publikation: Konferencebidrag uden forlag/tidsskriftKonferenceabstrakt til konferenceFormidling

Resumé

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.
OriginalsprogEngelsk
Publikationsdato14. jan. 2019
StatusUdgivet - 14. jan. 2019
BegivenhedNordic POP 1st Annual Meeting - Holmenkollen, Oslo, Norge
Varighed: 14. jan. 201916. jan. 2019

Konference

KonferenceNordic POP 1st Annual Meeting
LokationHolmenkollen
LandNorge
ByOslo
Periode14/01/201916/01/2019

Fingeraftryk

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

Citer dette

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 fra Nordic POP 1st Annual Meeting, Oslo, Norge.
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 fra Nordic POP 1st Annual Meeting, Oslo, Norge.
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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, Norge, 14/01/2019 - 16/01/2019, .

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

2019. Abstract fra Nordic POP 1st Annual Meeting, Oslo, Norge.

Publikation: Konferencebidrag uden forlag/tidsskriftKonferenceabstrakt til konferenceFormidling

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 fra Nordic POP 1st Annual Meeting, Oslo, Norge.