Inhibition of Mucosal Glycylsarcosine Uptake by Acetate in Rat Distal Small Intestine

Abstract

SUMMARY Acetate deriving from microbial fermentation may occur at considerable concentrations in the distal small intestine, where it appears to be absorbed by two different mechanisms: acetate‐HCO3− exchange and non‐ionic diffusion. Whether acetate affects absorption of other nutrients at this intestinal site is not known. Therefore the influence of acetate (30 mmol l−1) on oligopeptide absorption was studied using an in vitro mucosal uptake technique allowing measurement of substrate uptake across the brush border membrane (BBM). Acetate significantly inhibited mucosal uptake of 14C‐labelled glycylsarcosine (Gly‐Sar) at pH 6 and pH 7 in the presence of sodium. No inhibition occurred in the absence of sodium. Both acetate and the absence of sodium decreased Vmax of mucosal Gly‐Sar uptake without substantially affecting the apparent Km value. Since it is well established that Vmax of peptide transport across the intestinal BBM depends on the size of the transmembrane H+ gradient as a driving force the present findings are in accordance with the assumption that acetate inhibits peptide absorption by attenuating the H+ gradient across the BBM, which depends on the presence of sodium.

Enhanced Intestinal Absorption of Drugs by Activation of Peptide Transporter PEPT1 Using Proton‐Releasing Polymer

“…33,34 On the contrary, it was reported that a reduction of the pH of the incubation medium from pH 7.0 to pH 6.0 increased mucosal uptake of glycylsarcosine by PEPT1. 30 It seems likely that the pH in the microclimate as well as intestinal content can be decreased with the acidic polymer used in the present study. Accordingly, the strategy demonstrated in this study should be useful to activate the proton-coupled peptide transporter for improvement of the BA of peptidemimetic drugs that exhibit low absorption due to unfavorable conditions in the intestinal lumen, even if they are transported well by PEPT1 in vitro.…”

“…However, Scharrer et al reported that acetate significantly inhibited mucosal uptake of [ 14 C]glycylsarcosine mediated by PEPT1. 30 Thus, we considered that Eudragit L100-55 would be more suitable than small acidic molecules for controlling intestinal pH, especially in the lower part of the small intestine, where the pH is higher than in the upper and middle parts of the intestine, and the PEPT1 expression is highest. 16 When Eudragit L100-55 was added to an ileal closed loop, where the pH in the lumen increased significantly during a similar experiment without the polymer, 16 the pH in the luminal solution was decreased in an Eudragit L100-55 concentrationdependent manner ( Figure 3B and 3D), and the absorption of cefadroxil and cefixime from the loop was increased in the presence of the acidic polymer ( Figure 3A and 3C).…”