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.

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 µM). 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 µM, 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 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 [(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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport / drug effects*
  • Cell Line
  • Drug Interactions / physiology
  • Estrone / analogs & derivatives
  • Estrone / metabolism
  • HEK293 Cells
  • Humans
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Methotrexate / pharmacology*
  • Organic Anion Transport Protein 1 / metabolism
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Proton Pump Inhibitors / pharmacology*
  • p-Aminohippuric Acid / metabolism

Substances

  • Organic Anion Transport Protein 1
  • Organic Anion Transporters, Sodium-Independent
  • Proton Pump Inhibitors
  • organic anion transport protein 3
  • Estrone
  • estrone sulfate
  • p-Aminohippuric Acid
  • Methotrexate