title: Ibuprofen is a non-competitive inhibitor of the peptide transporter hPEPT1 (SLC15A1): possible interactions between hPEPT1 substrates and ibuprofen.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors: Department of Pharmaceutics and Analytical Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Diana Højmark
authors: DH
authors: Omkvist
authors: Birger
authors: B
authors: Brodin
authors: Carsten Uhd
authors: CU
authors: Nielsen
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D018938:Caco-2 Cells; D002460:Cell Line; D002461:Cell Line, Transformed; D004151:Dipeptides / Q000378:metabolism; D004285:Dogs; D004347:Drug Interactions; D005998:Glycine / Q000378:metabolism; D006801:Humans; D007052:Ibuprofen / Q000493:pharmacokinetics / Q000494:pharmacology*; D008757:Methylglucosides / Q000493:pharmacokinetics; D000074011:Peptide Transporter 1; D027981:Symporters / Q000037:antagonists & inhibitors*
chemical_list: D004151:Dipeptides; D008757:Methylglucosides; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters; C004194:glycylsarcosine; C027020:methylglucoside; D005998:Glycine; D007052:Ibuprofen