Intestinal Absorption Mechanisms of .BETA.-Lactam Antibiotics.

Abstract

There are remarkable differences in oral bioavailabilities among β-lactam antibiotics, ranging from poorly absorbed to completely absorbed, despite that most of these drugs posses similar degrees of hydrophilicity. Many of the well-absorbed β-lactam antibiotics have been shown to be substrates for the transport system by which peptides are absorbed (proton-coulpled transporter, Pep Tl), whereas the poorly absorbed analogs are not. Although the proton-coupled transport system has the greatest influence on intestinal absorption of β-lactam antibiotics, passive diffusion contributes significantly to the total transport. Considerling that passive diffusion of some β-lactam antibiotics is fairly rapid, the low oral bioavailability of other related compound, like cefazolin, could seem inconsistent. Recently, it has been found that the mechanisms which induce secretory-oriented permeation of orally inactive β-lactam antibiotics are factors limiting intestinal absorption of such antibiotics. This energy-demanding effiux system is distinct from P-glycoprotein-mediated transport. It should be noted that as long as a β-lactam antibiotic is the substrate with a high affinity for this intestiinal effiux system, the efflux system can pump it out efficiently from cytosol, even if an absorptive peptide transport system on the brush-border membrane mediates their translocation from the lumen into cytosol. Previously, we reported that the well-absorbed β-lactam antibiotics bind to the cytosolic component, fraction b, extensively, whereas the orally inactive analogs do not bind to this fraction. Therefore, it may be possible that the well-absorbed β-lactam antibiotics have a way to escape the intestinal effiux system; for example, binding to the fraction b could prevent the well-absorbed β-lactam antibiotics from interacting with the energy-dependent efflux system, stimulating absorption of these antibiotics. The role of the binding factor, fraction b, for intestinal absorption mechanisms should be evaluated in more detail.