Proton pump inhibitors inhibit methotrexate transport by renal basolateral organic anion transporter hOAT3.

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Chioukh R, Noel-Hudson MS, Ribes S, Fournier N, Becquemont L, Verstuyft C

Proton pump inhibitors inhibit methotrexate transport by renal basolateral organic anion transporter hOAT3.

Drug Metab Dispos. 2014 Dec;42(12):2041-8. doi: 10.1124/dmd.114.058529. Epub 2014 Sep 19.

PubMed ID

25239859 [ View in PubMed

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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 [(3)H]estrone sulfate (ES), [(3)H]p-aminohippuric acid (PAH), and [(3)H]MTX uptake in vitro. hOAT3 is a high affinity transporter for MTX (Km = 21.17 +/- 5.65 microM). Omeprazole, lansoprazole, and pantoprazole inhibited [(3)H]MTX uptake in HEK-hOAT3 cells with an IC50 of 6.8 +/- 1.16, 1.14 +/- 0.26, and 4.45 +/- 1.62 microM, respectively, and inhibited the [(3)H]ES uptake in HEK-hOAT3 cells with an IC50 of 20.59 +/- 4.07, 3.96 +/- 0.96, and 7.89 +/- 2.31 microM, 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 microM, respectively). These in vitro results suggest that PPIs inhibit [(3)H]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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Esomeprazole	Solute carrier family 22 member 8	Protein	Humans	Unknown	Inhibitor	Details
Pantoprazole	Solute carrier family 22 member 8	Protein	Humans	Unknown	Inhibitor	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
Methotrexate Pantoprazole	The excretion of Methotrexate can be decreased when combined with Pantoprazole.
Methotrexate Rabeprazole	The excretion of Methotrexate can be decreased when combined with Rabeprazole.
Methotrexate Dexlansoprazole	The excretion of Methotrexate can be decreased when combined with Dexlansoprazole.
Methotrexate Dexrabeprazole	The excretion of Methotrexate can be decreased when combined with Dexrabeprazole.
Methotrexate Ilaprazole	The excretion of Methotrexate can be decreased when combined with Ilaprazole.