title: Transport mechanisms responsible for the absorption of loracarbef, cefixime, and cefuroxime axetil into human intestinal Caco-2 cells.
abstract: Loracarbef, cefixime and cefuroxime axetil are beta-lactam antibiotics that are administered orally. Oral absorption of loracarbef is nearly complete, while that of cefixime and cefuroxime axetil is 30-50%. To investigate this we used the human intestinal cell line Caco-2 that possesses the proton-dependent peptide transporter that takes up cephalexin and cefaclor. Drug uptake was measured at pH 6 by high performance liquid chromatography or with radioactively labelled drug. The initial uptake rate of 1 mM cefixime was lower than that of 1 mM loracarbef. By 2 h both drugs were concentrated intracellularly against a gradient; however, the accumulation of cefixime was only 40% of that of loracarbef. The uptake rate of both drugs was sodium-independent, temperature- and energy-dependent, and was inhibited by dipeptides, cephalexin, cefaclor, but not by amino acids. Kinetic analysis of the concentration-dependence of the uptake rates for loracarbef and cefixime indicated that diffusion and a single transport system were responsible for uptake. The kinetic parameters for loracarbef and cefixime, respectively, were: Km values of 8 and 17 mM and Vmax values of 6.5 and 2 nmol/min per mg protein. Loracarbef and cefixime were competitive inhibitors of each other's uptake. By contrast, cefuroxime axetil was taken up and rapidly hydrolyzed to cefuroxime by Caco-2 cells. Cefuroxime axetil uptake was not dependent on energy and was not affected by dipeptides. Thus, cefuroxime axetil apparently enters Caco-2 cells by simple diffusion. By contrast, loracarbef and cefixime share a common transport mechanism, the proton-dependent dipeptide transporter. Cefixime was taken up less well than loracarbef due to a substantial reduction in the turnover rate and decreased affinity of the transporter for cefixime.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285-0424.
authors.forename: A H
authors.initials: AH
authors.lastname: Dantzig
authors.forename: D C
authors.initials: DC
authors.lastname: Duckworth
authors.forename: L B
authors.initials: LB
authors.lastname: Tabas
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000596:Amino Acids / Q000494:pharmacology; D001692:Biological Transport; D020682:Cefixime; D002439:Cefotaxime / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002444:Cefuroxime / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002511:Cephalosporins / Q000493:pharmacokinetics*; D003110:Colonic Neoplasms / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004336:Drug Antagonism; D004734:Energy Metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D002511:Cephalosporins; D004151:Dipeptides; C054920:loracarbef; D020682:Cefixime; D002439:Cefotaxime; D002444:Cefuroxime; C040738:cefuroxime axetil