NONCOMPETITIVE INHIBITION OF CEPHRADINE UPTAKE BY ENALAPRIL IN RABBITINTESTINAL BRUSH-BORDER MEMBRANE-VESICLES - AN ENALAPRIL SPECIFIC INHIBITORY BINDING-SITE ON THE PEPTIDE CARRIER

ACE inhibitors, as well as aminocephalosporins with peptide-like struc tures, are transported by the intestinal peptide carrier. We investiga ted the transport mechanism using intestinal brush-border membrane ves icles from rabbits and observed that enalapril, an angiotensin convert ing enzyme inhibitor and substrate of the peptide carrier, noncompetit ively inhibited the uptake of cephradine, an aminocephalosporin and su bstrate of the peptide carrier, with an inhibition constant (K-i) of 2 .6 mM when it was present on the cis side (outside) of the vesicles. B y contrast, enalaprilat, cefadroxil and GlyPro competitively inhibited cephradine transport with K-i values of 5.4, 3.8 and 5.1, respectivel y. These results suggest the presence of an enalapril-specific inhibit ory binding site on the peptide carrier. In addition, enalapril on the trans side (inside) of the vesicles inhibited the uptake of cephradin e, suggesting an apparent reduction of carrier availability by a trapp ing mechanism. On the other hand, cefadroxil stimulated the uptake of cephradine in the trans experiment, consistent with the concept of cou ntertransport. These findings reveal the uniqueness of enalapril regar ding its mode of interaction with the peptide carrier(s) which has bee n of increasing interest regarding its role in the intestinal absorpti on of peptide-type drugs.