Characterization of the oral absorption of beta-lactam antibiotics. II. Competitive absorption and peptide carrier specificity.

The beta-lactam antibiotic oral absorption pathway is studied using a single-pass perfusion technique in the rat small intestine. Beta-lactam antibiotic absorption in the presence of amino acids, small peptides, and other beta-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 beta-lactam antibiotic intestinal carrier system. Several concentrations of cephalexin, coperfused 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; Jmax remained unchanged at 9.2 (+/- 1.2) and 11.1 (+/- 2.1) mM; and the carrier permeability, Pc, was reduced by approximately 50% from 1.11 (+/- 0.10) to 0.59 (+/- 0.04), consistent with competitive absorption kinetics. The predicted in situ wall permeability, the mean value of P*w, of beta-lactams perfused in the presence of other beta-lactams was calculated and then compared with experimentally determined values. For cefadroxil, P*w = 0.27 (+/- 0.04), the mean value of P*w = 0.29; for cefatrizine, P*w = 0.67 (+/- 0.09), the mean value of P*w (+/- 0.09), the mean value of P*w = 0.59; and for cephalexin, P*w = 0.56 (+/- 0.05), the mean value of P*w = 0.59.(ABSTRACT TRUNCATED AT 250 WORDS)