Characterization of the Oral Absorption of β-Lactam Antibiotics II: Competitive Absorption and Peptide Carrier Specificity

Abstract

The β-lactam antibiotic oral absorption pathway is studied using a single-pass perfusion technique in the rat small intestine. β-Lactam antibiotic absorption in the presence of amino acids, small peptides, and other β-lactams is modeled using a simple competitive inhibition boundary condition at the intestinal wall, with a corrected value for the intestinal wall concentration, Cw derived from the modified boundary layer analysis. The model-predicted permeability in the presence of an inhibitor is used to characterize the β-lactam antibiotic intestinal carrier system. Several concentrations of cephalexin, co-perfused with a constant concentration of cefadroxil (equal to its Km), showed that the Km of cephalexin approximately doubled from 7.2 (±1.1) to 18.8 (±4.1) mM; J*max remained unchanged at 9.2 (±1.2) and 11.1 (±2.1) mM; and the carrier permeability, <P*c, was reduced by ~50% from 1.11 (±0.10) to 0.59 (±0.04), consistent with competitive absorption kinetics. The predicted in situ wall permeability, <P*w>, of β-lactams perfused in the presence of other β-lactams was calculated and then compared with experimentally determined values. For cefadroxil, <P*w >, = 0.27 (±0.04), <P*w > = 0.29; for cefatrizine, <P*w >, = 0.67 (±0.09), <P*w > = 0.59; and for cephalexin, <P*w >, = 0.56 (±0.05), <P*w > = 0.59. The characteristics of the β-lactam intestinal carrier system were further studied by co-perfusing β-lactams with several di- or tripeptides, which resulted in a significant decrease in β-lactam permeability, whereas co-perfusion with amino acids did not decrease β-lactam permeability. These results strongly support β-lactam absorption by the intestinal peptide transport system in rats. Moreover, these results, consistent with simple competitive inhibition, indicate that macroscopic absorption parameters may be useful for predicting drug–drug and possibly food–drug absorption interactions in the gastrointestinal tract of humans.