Characterization of the Oral Absorption of β-Lactam Antibiotics. I. Cephalosporins: Determination of Intrinsic Membrane Absorption Parameters in the Rat Intestine In Situ

Abstract

The oral absorption of five cephalosporin antibiotics, cefaclor, cefadroxil, cefatrizine, cephalexin, and cephradine, has been studied using a single-pass intestinal perfusion technique in rats. Intrinsic membrane absorption parameters, “unbiased” by the presence of an aqueous permeability (diffusion or stagnant layer), have been calculated utilizing a boundary layer mathematical model. The resultant intrinsic membrane absorption parameters are consistent with a significant carrier-mediated, Michaelis-Menten-type kinetic mechanism and a small passive component in the jejunum. Cefaclor colon permeability is low and does not exhibit concentration dependent behavior. The measured carrier parameters (±SD) for the jejunal perfusions are as follows: cefaclor, J max * = 21.3 (±4.0), K m = 16.1 (±3.6), P m * = 0, and P c * = 1.32 (±0.07); cefadroxil, J max * = 8.4 (±0.8), K m = 5.9 (±0.8), P m * = 0, and P c * = 1.43 (±0.10); cephalexin, J max * = 9.1 (±1.2), K m = 7.2 (±1.2), P m * = 0, and P c * = 1.30 (±0.10); cefatrizine, J max * = 0.73 (±0.19), K m = 0.58 (±0.17), P m * = 0.17 (±0.03), and P c * = 1.25 (±0.10); and cephradine, J max * = 1.57 (±0.84), K m = 1.48 (±0.75), P m * = 0.25 (±0.07), and P c * = 1.06 (±0.08). The colon absorption parameter for cefaclor is P m * = 0.36 (±0.06, where J max * (m M ) is the maximal flux, K m (m M ) is the Michaelis constant, P m * is the passive membrane permeability, and P c *is the carrier permeability. Aminocephalosporin perfusion results indicate that jejunal absorption in the rat occurs by a nonpassive process, with some of the compounds possessing a small but statistically significant passive component, while the colon permeability is low and follows a simple passive absorption mechanism.