Ibuprofen is a non-competitive inhibitor of the peptide transporter hPEPT1 (SLC15A1): possible interactions between hPEPT1 substrates and ibuprofen

Br J Pharmacol. 2010 Dec;161(8):1793-805. doi: 10.1111/j.1476-5381.2010.01000.x.


Background and purpose: Recently, we identified etodolac as a possible ligand for the human intestinal proton-couple peptide transporter (hPEPT1). This raised the possibility that other non-steroidal anti-inflammatory drugs, and especially ibuprofen, could also interact with hPEPT1. Here, we have assessed the interactions of ibuprofen with hPEPT1.

Experimental approach: The uptake of [(14)C]Gly-Sar, [(3)H]Ibuprofen and other radio-labelled compounds were investigated in Madin-Darby canine kidney cells (MDCK)/hPEPT1, MDCK/Mock, LLC-PK(1) or Caco-2 cells. The transepithelial transport of ibuprofen and hPEPT1 substrates was investigated in Caco-2 cell monolayers.

Key results: Ibuprofen concentration dependently inhibited hPEPT1-mediated uptake of Gly-Sar in MDCK/hPEPT1 cells (K(i)(app) = 0.4 mM) but uptake of ibuprofen in Caco-2 cells and MDCK/hPEPT1 cells was not inhibited by hPEPT1 substrates. The maximum uptake rate for Gly-Sar uptake was reduced from 522 pmol·min(-1)·cm(-2) to 181 pmol·min(-1)·cm(-2) and 78 pmol·min(-1)·cm(-2) in the presence of 0.5 mM and 1 mM ibuprofen, respectively. The interaction between ibuprofen and hPEPT1 was thus non-competitive. In LLC-PK1 cells, ibuprofen (1 mM) did not influence the transporter-mediated uptake of glycine or α-methyl-D-glycopyranoside. In Caco-2 cell monolayers the absorptive transport of δ-aminolevulinic acid was reduced by 23% and 48% by ibuprofen (1 and 10 mM), respectively. Likewise the transport of Gly-Sar was reduced by 23% in the presence of ibuprofen (1 mM).

Conclusions and implications: Ibuprofen is a non-competitive inhibitor of hPEPT1. As ibuprofen reduced the transepithelial transport of δ-aminolevulinic acid, drug-drug interactions between ibuprofen and hPEPT1 drug substrates at their site of absorption are possible if administered together.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / drug effects*
  • Caco-2 Cells
  • Cell Line
  • Cell Line, Transformed
  • Dipeptides / metabolism
  • Dogs
  • Drug Interactions
  • Glycine / metabolism
  • Humans
  • Ibuprofen / pharmacokinetics
  • Ibuprofen / pharmacology*
  • Methylglucosides / pharmacokinetics
  • Peptide Transporter 1
  • Symporters / antagonists & inhibitors*


  • Dipeptides
  • Methylglucosides
  • Peptide Transporter 1
  • SLC15A1 protein, human
  • Symporters
  • glycylsarcosine
  • methylglucoside
  • Glycine
  • Ibuprofen