title: Relevance of PepT1 in the intestinal permeability and oral absorption of cefadroxil.
abstract: OBJECTIVE
  To determine the contribution of intestinal PepT1 on the permeability and oral absorption of the β-lactam antibiotic drug cefadroxil.
  
  
  METHODS
  The effective permeability (P eff ) of cefadroxil was evaluated in wild-type and PepT1 knockout mice following in situ single-pass intestinal perfusions. The plasma concentration-time profiles of cefadroxil were also examined after oral gavage.
  
  
  RESULTS
  The P eff (cm/s) of cefadroxil in wild-type mice was 0.49 × 10(-4) in duodenum, 0.80 × 10(-4) in jejunum, 0.88 × 10(-4) in ileum and 0.064 × 10(-4) in colon. The P eff (cm/s) in PepT1 knockout mice was significantly reduced in small intestine, but not in colon, as shown by values of 0.003 × 10(-4), 0.090 × 10(-4), 0.042 × 10(-4) and 0.032 × 10(-4), respectively. Jejunal uptake of cefadroxil was saturable (Km = 2-4 mM) and significantly attenuated by the sodium-proton exchange inhibitor 5-(N,N-dimethyl)amiloride. Jejunal permeability of cefadroxil was not affected by L-histidine, glycine, cephalothin, p-aminohippurate or N-methylnicotinamide. In contrast, cefadroxil permeability was significantly reduced by glycylproline, glycylsarcosine, or cephalexin. Finally, PepT1 ablation resulted in 23-fold reductions in peak plasma concentrations and 14-fold reductions in systemic exposure of cefadroxil after oral dosing.
  
  
  CONCLUSIONS
  The findings are definitive in demonstrating that PepT1 is the major transporter responsible for the small intestinal permeability of cefadroxil as well as its enhanced oral drug performance.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-5633, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Posada
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D002434:Cefadroxil / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D055786:Gene Knockout Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000074011:Peptide Transporter 1; D010539:Permeability; D027981:Symporters / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000074011:Peptide Transporter 1; C489941:Slc15a1 protein, mouse; D027981:Symporters; D002434:Cefadroxil