Abstract

ACE inhibitors, as well as aminocephalosporins with peptide-like structures, are transported by the intestinal peptide carrier. We investigated the transport mechanism using intestinal brush-border membrane vesicles from rabbits and observed that enalapril, an angiotensin converting enzyme inhibitor and substrate of the peptide carrier, noncompetitively inhibited the uptake of cephradine, an aminocephalosporin and substrate of the peptide carrier, with an inhibition constant (Ki) of 2.6 mM when it was present on the cis side (outside) of the vesicles. By contrast, enalaprilat, cefadroxil and GlyPro competitively inhibited cephradine transport with Ki values of 5.4, 3.8 and 5.1, respectively. These results suggest the presence of an enalapril-specific inhibitory binding site on the peptide carrier. In addition, enalapril on the trans side (inside) of the vesicles inhibited the uptake of cephradine, suggesting an apparent reduction of carrier availability by a trapping mechanism. On the other hand, cefadroxil stimulated the uptake of cephradine in the trans experiment, consistent with the concept of countertransport. These findings reveal the uniqueness of enalapril regarding its mode of interaction with the peptide carrier(s) which has been of increasing interest regarding its role in the intestinal absorption of peptide-type drugs.