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

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 [C-14]Gly-Sar, [H-3]Ibuprofen and other radio-labelled compounds were investigated in Madin-Darby canine kidney cells (MDCK)/hPEPT1, MDCK/Mock, LLC-PK1 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 alpha-methyl-D-glycopyranoside. In Caco-2 cell monolayers the absorptive transport of delta-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 delta-aminolevulinic acid, drug-drug interactions between ibuprofen and hPEPT1 drug substrates at their site of absorption are possible if administered together.