Stereoselective uptake of β‐lactam antibiotics by the intestinal peptide transporter

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Abstract
1 The stereoselective transport of β-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 β-lactam, [3H]-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 β-lactams not only bind to the peptide transporter with high affinity but are indeed transported. 4 Efficient proton-coupled transport of L-β-lactam antibiotics was also shown to occur in Xenopus laevis oocytes expressing the cloned peptide transporter PepTl from rabbit small intestine. 5 Both cell systems therefore express a stereoselective transport pathway for β-lactam antibiotics with very similar characteristics and may prove useful for screening rapidly the oral availability of peptide-derived drugs.