Intestinal transport of beta-lactam antibiotics: Analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco-2 cell monolayersand the transepithelial flux

Purpose. This study on the intestinal transport of p-lactam antibiotics was undertaken to investigate the correlation between cellular transport param eters and the bioavailability. Methods. Transport of 23 beta-lactam antibiotics was characterized by measu ring their ability to inhibit the uptake of glycylsarcosine into Caco-2 cel ls, their uptake into the cells and their total flux across the cell monola yers. Results. Ceftibuten and cyclacillin were recognized by PEPT1 with affinity constants comparable to those of natural dipeptides (K-i = 0.3 and 0.5 mM, respectively). Cefadroxil, cefamandole, cephradine, cefaclor, cefuroxime-ax etil, cefixime, cephalotin, cephalexin and ampicillin also interacted with PEPT1 (K-i = 7-14 mM). In contrast, cefapirin, cefodizime, cefuroxime, cefm etazole, ceftazidime, benzylpenicillin, ceftriaxone, cefpirome, cefotaxime, cefepime, cephaloridine and cefsulodin displayed no affinity to the transp ort system (K-i > 20 mM). The uptake into the cells and the transepithelial flux was highest for those beta-lactam antibiotics, which showed the stron gest inhibition of [C-14]Gly-Sar transport (p < 0.0001). Exceptions were ce furoximaxetil and cephalotin. Conclusions. The probability of oral bioavailability for beta-lactam antibi otics is mainly determined by their affinity to PEPT1. A threshold K-i valu e of 14 mM with respect to Gly-Sar uptake is required.