title: Stereoselective uptake of beta-lactam antibiotics by the intestinal peptide transporter.
abstract: 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, [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 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.
authors.affiliation: Institute of Nutritional Sciences, University of Giessen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Wenzel
authors.forename: D T
authors.initials: DT
authors.lastname: Thwaites
authors.forename: H
authors.initials: H
authors.lastname: Daniel
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015820:Cadherins; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002506:Cephalexin / Q000494:pharmacology; D002511:Cephalosporins / Q000378:metabolism / Q000494:pharmacology; D006868:Hydrolysis; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008845:Microinjections; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D013237:Stereoisomerism; D014982:Xenopus laevis
chemical_list: D000900:Anti-Bacterial Agents; C490584:CDH17 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D002511:Cephalosporins; D026901:Membrane Transport Proteins; D010455:Peptides; C067802:intestinal peptide-proton cotransporter; C054920:loracarbef; D002506:Cephalexin