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Research ArticleArticle

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

Rym Chioukh, Marie-Sophie Noel-Hudson, Sandy Ribes, Natalie Fournier, Laurent Becquemont and Celine Verstuyft
Drug Metabolism and Disposition December 2014, 42 (12) 2041-2048; DOI: https://doi.org/10.1124/dmd.114.058529
Rym Chioukh
EA 4123 Barrières Physiologiques et Réponses Thérapeutiques (R.C., M.-S.N.-H., S.R., L.B., C.V.) and EA 4529 Lipides Membranaires et Régulation Fonctionnelle du Cœur et des Vaisseaux (N.F.), Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Centre de Recherche Clinique Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (L.B.); and Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (C.V.)
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Marie-Sophie Noel-Hudson
EA 4123 Barrières Physiologiques et Réponses Thérapeutiques (R.C., M.-S.N.-H., S.R., L.B., C.V.) and EA 4529 Lipides Membranaires et Régulation Fonctionnelle du Cœur et des Vaisseaux (N.F.), Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Centre de Recherche Clinique Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (L.B.); and Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (C.V.)
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Sandy Ribes
EA 4123 Barrières Physiologiques et Réponses Thérapeutiques (R.C., M.-S.N.-H., S.R., L.B., C.V.) and EA 4529 Lipides Membranaires et Régulation Fonctionnelle du Cœur et des Vaisseaux (N.F.), Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Centre de Recherche Clinique Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (L.B.); and Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (C.V.)
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Natalie Fournier
EA 4123 Barrières Physiologiques et Réponses Thérapeutiques (R.C., M.-S.N.-H., S.R., L.B., C.V.) and EA 4529 Lipides Membranaires et Régulation Fonctionnelle du Cœur et des Vaisseaux (N.F.), Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Centre de Recherche Clinique Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (L.B.); and Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (C.V.)
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Laurent Becquemont
EA 4123 Barrières Physiologiques et Réponses Thérapeutiques (R.C., M.-S.N.-H., S.R., L.B., C.V.) and EA 4529 Lipides Membranaires et Régulation Fonctionnelle du Cœur et des Vaisseaux (N.F.), Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Centre de Recherche Clinique Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (L.B.); and Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (C.V.)
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Celine Verstuyft
EA 4123 Barrières Physiologiques et Réponses Thérapeutiques (R.C., M.-S.N.-H., S.R., L.B., C.V.) and EA 4529 Lipides Membranaires et Régulation Fonctionnelle du Cœur et des Vaisseaux (N.F.), Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France; Centre de Recherche Clinique Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (L.B.); and Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, France (C.V.)
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Abstract

The coadministration of methotrexate (MTX) and proton pump inhibitors (PPIs) can result in a pharmacokinetic interaction that delays MTX elimination and subsequently increases the MTX blood concentrations. Human organic anion transporters (hOATs) are responsible for the renal tubular secretion of MTX and are thought to be involved in this drug interaction. The aim of this study was to evaluate the inhibitory potencies of PPIs on hOAT1 and hOAT3, which are the two isoforms of OATs predominantly expressed in kidney proximal tubules. Using stably transfected cell systems that express the uptake transporters human embryonic kidney (HEK)-hOAT1 and HEK-hOAT3, we analyzed the inhibitory potencies of omeprazole, lansoprazole, and pantoprazole on OAT-mediated [3H]estrone sulfate (ES), [3H]p-aminohippuric acid (PAH), and [3H]MTX uptake in vitro. hOAT3 is a high affinity transporter for MTX (Km = 21.17 ± 5.65 µM). Omeprazole, lansoprazole, and pantoprazole inhibited [3H]MTX uptake in HEK-hOAT3 cells with an IC50 of 6.8 ± 1.16, 1.14 ± 0.26, and 4.45 ± 1.62 µM, respectively, and inhibited the [3H]ES uptake in HEK-hOAT3 cells with an IC50 of 20.59 ± 4.07, 3.96 ± 0.96, and 7.89 ± 2.31 µM, respectively. Furthermore, omeprazole, lansoprazole, and pantoprazole exhibited inhibited PAH uptake on hOAT1 in a concentration-dependent manner (IC50 = 4.32 ± 1.26, 7.58 ± 1.06, and 63.21 ± 4.74 µM, respectively). These in vitro results suggest that PPIs inhibit [3H]MTX transport via hOAT3 inhibition, which most likely explains the drug-drug interactions between MTX and PPIs and should be considered for other OATs substrates.

Footnotes

    • Received April 18, 2014.
    • Accepted September 19, 2014.
  • Rym Chioukh started this work with funding from the Ecole Doctorale 425 Université Paris Sud for her Ph.D.

  • dx.doi.org/10.1124/dmd.114.058529.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (12)
Drug Metabolism and Disposition
Vol. 42, Issue 12
1 Dec 2014
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Research ArticleArticle

Drug Interaction between MTX with PPIs and Renal Transporters

Rym Chioukh, Marie-Sophie Noel-Hudson, Sandy Ribes, Natalie Fournier, Laurent Becquemont and Celine Verstuyft
Drug Metabolism and Disposition December 1, 2014, 42 (12) 2041-2048; DOI: https://doi.org/10.1124/dmd.114.058529

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Research ArticleArticle

Drug Interaction between MTX with PPIs and Renal Transporters

Rym Chioukh, Marie-Sophie Noel-Hudson, Sandy Ribes, Natalie Fournier, Laurent Becquemont and Celine Verstuyft
Drug Metabolism and Disposition December 1, 2014, 42 (12) 2041-2048; DOI: https://doi.org/10.1124/dmd.114.058529
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