Effects of fatty acid glycerol esters on intestinal absorptive and secretory transport of ceftibuten.

Abstract

The effects of fatty acid glycerol esters and Tweens on the intestinal transport of ceftibuten were studied using a diffusion chamber system. The apparent permeation coefficient (P(app)) was used as an index of the mucosal permeability to ceftibuten. The P(app) markedly increased by the addition of hexaglycerol monostearate (HGMS) or hexaglycerol sesquistearate (HGSS) under an H+-gradient condition, while hexaglycerol tristearate (HGTS) and Tweens showed no effect on the absorptive ceftibuten permeability. These results are in agreement with those obtained in the previous study in the brush-border membrane vesicles. On the other hand, in the absence of an H+-gradient, the S-to-M transport of ceftibuten was proven to be significantly higher than the M-to-S one. In addition, either ATP-depletion of the mucosa or the addition of probenecid proved to enhance significantly the permeability of ceftibuten. These findings suggest the existence of an active secretory transport system for ceftibuten in the jejunal mucosa. To estimate potential effects of glycerol esters on efflux pumps as well as peptide transporters, the mucosal-to-serosal (M-to-S) and serosal-to-mucosal (S-to-M) permeability in the presence of the esters was further examined. HGMS, HGSS and HGTS markedly enhanced the M-to-S but not the S-to-M transport in the ATP-depleted jejunum without an H+-gradient, in which conditions contributions of both peptide transporter and efflux pump should be substantially small. HGMS and HGSS significantly enhanced the M-to-S ceftibuten transport in the ATP-depleted jejunum with an H+-gradient (p<0.01 vs. M-to-S transport without surfactant under the same conditions). Whereas, these glycerol esters were found hardly to affect the P(app) of the S-to-M transport. These results indicate that the enhanced intestinal transport of ceftibuten due to the glycerol esters may be based on their effects on peptide transporters but neither on efflux pumps nor on the passive permeation routes.