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 [ 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.