STEREOSELECTIVE UPTAKE OF BETA-LACTAM ANTIBIOTICS BY THE INTESTINAL PEPTIDE TRANSPORTER

1 The stereoselective transport of beta-lactam antibiotics has been investigated in the human intestinal epithelial cell line, Caco-2, by use of D- and L-enantiomers of cephalexin and loracarbef as substrates. 2 The L-isomers of cephalexin, loracarbef and dipeptides displayed a higher affinity for the oligopeptide/H+-symporter in Caco-2 cells than the D-isomers. This was demonstrated by inhibition of the influx of the beta-lactam, [H-3]-cefadroxil. 3 By measurement of the substrate-induced intracellular acidification in Caco-2 cells loaded with the pH-sensitive fluorescent dye BCECF (2',7'-bis(2-carboxyethyl)-5-(6)-carboxy-fluorescein), it was demonstrated for the first time that L-isomers of beta-lactams not only bind to the peptide transporter with high affinity but are indeed transported. 4 Efficient proton-coupled transport of L-beta-lactam antibiotics was also shown to occur in Xenopus laevis oocytes expressing the cloned peptide transporter PepT1 from rabbit small intestine. 5 Both cell systems therefore express a stereoselective transport pathway for beta-lactam antibiotics with very similar characteristics and may prove useful for screening rapidly the oral availability of peptide-derived drugs.