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

Purpose. This study on the intestinal transport of p-lactam antibiotics was undertaken to investigate the correlation between cellular transport parameters and the bioavailability. Methods. Transport of 23 beta-lactam antibiotics was characterized by measuring their ability to inhibit the uptake of glycylsarcosine into Caco-2 cells, their uptake into the cells and their total flux across the cell monolayers. 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-axetil, cefixime, cephalotin, cephalexin and ampicillin also interacted with PEPT1 (K-i = 7-14 mM). In contrast, cefapirin, cefodizime, cefuroxime, cefmetazole, ceftazidime, benzylpenicillin, ceftriaxone, cefpirome, cefotaxime, cefepime, cephaloridine and cefsulodin displayed no affinity to the transport system (K-i > 20 mM). The uptake into the cells and the transepithelial flux was highest for those beta-lactam antibiotics, which showed the strongest inhibition of [C-14]Gly-Sar transport (p < 0.0001). Exceptions were cefuroximaxetil and cephalotin. Conclusions. The probability of oral bioavailability for beta-lactam antibiotics is mainly determined by their affinity to PEPT1. A threshold K-i value of 14 mM with respect to Gly-Sar uptake is required.