Abstract

The transport characteristics of p.o. cephalosporin antibiotics by monolayers of the human intestinal epithelial cell line Caco-2 were examined by measuring intracellular accumulation and transcellular transport. In the presence of an inward H+ gradient (at pH 6.0 of the apical medium), cephalosporins were accumulated by the monolayers in the following order: ceftibuten (anion) > cephradine (zwitterion) > cephalexin (zwitterion) > cefixime (anion). The accumulation rate of ceftibuten was more rapid than that of cephradine, whereas both appeared at the same rate in the basolateral compartment. The efflux of ceftibuten from the monolayers to the basolateral compartment was lower than the efflux of cephradine. The accumulation rate of ceftibuten from the basolateral side was markedly lower than that of cephradine. The accumulation of ceftibuten from both the apical and basolateral compartment was significantly inhibited by excess dipeptides. The kinetic parameters indicated that ceftibuten has higher affinity for the apical dipeptide transport system in the presence of a pH gradient, whereas it has much lower affinity for the basolateral dipeptide transport system at physiological pH of 7.4 than cephradine. These results suggest that both cephradine and ceftibuten are transported via the H+/dipeptide cotransport system localized in the apical membranes, and that the flux of these drugs across the basolateral membranes is also mediated by the dipeptide transport system in an H+ gradient-independent manner, exhibiting a rate-limiting step for their transcellular transport in Caco-2 monolayers.