A COMPARISON OF THE AFFINITIES OF DIPEPTIDES AND ANTIBIOTICS FOR THE DIPEPTIDE/TRIPEPTIDE TRANSPORTER IN CACO-2 CELLS

The intestinal peptide transporter(s) is involved in the absorption of natural di-/tripeptides and peptidomimetic drugs. Several key aspects of peptide transport such as number of peptide transporters and structural requirements for transport via this carrier(s) are not fully understood. In addition, recent studies showed that interaction with the di-/tripeptide transporter(s) does not necessarily lead to transcellular transport. The variety of structures which appear to interact with the transporter could be explained by the presence of several transporters or by multiple binding sites in a single transporter. The objective of this study was to determine whether there is a clear difference between dipeptides and amino-p-lactam antibiotics which may suggest the involvement of different transporters/binding sites. Experiments were carried out in Caco-2 cell monolayers grown on microporous membranes using cephalexin as the model compound. Inhibition constants (K-1) were calculated from Dixon plots assuming competitive inhibition. The strong correlation between K-i and IC50 (independently determined) indicates that the assumption of competitive inhibition was probably correct. Results show: (a) that dipeptides have greater affinity for the cephalexin transporter(s) than antibiotics; (b) among dipeptides, neutral dipeptides seem to have higher affinity for the carrier; and (c) a relationship between affinity for the transporter(s) and transepithelial transport could not be found.