Restricted intestinal absorption of some beta-lactam antibiotics by an energy-dependent efflux system in rat intestine

Saitoh, H.; Fujisaki, H.; Aungst, B.J.; Miyazaki, K.

Pharmaceutical Research 14(5): 645-649


ISSN/ISBN: 0724-8741
PMID: 9165537
DOI: 10.1023/a:1012113430539
Accession: 009350769

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Purpose: The purpose of this study was to examine factors limiting the intestinal absorption of orally inactive beta-lactam antibiotics. Methods: Permeation behaviors of various beta-lactam antibiotics across rat intestinal segments were evaluated in vitro using diffusion cell. Results: Poorly absorbed beta-lactam antibiotics, like cephaloridine and cefoperazone, commonly exhibit greater serosal-to-mucosal permeation than mucosal-to-serosal permeation, while cephalexin permeation was greater in the mucosal-to-serosal direction. In the absence D-glucose, secretory-oriented permeation of cephaloridine and cefoperazone disappeared. Addition of sodium azide into an experimental buffer including D-glucose significantly and selectively enhanced mucosal-to-serosal permeation of cephaloridine and cefoperazone. Although benzylpenicillin, ampicillin, and amoxicillin all showed secretory-oriented permeation, the tendency to permeation was greatest with benzylpenicillin and least with amoxicillin. Probenecid stimulated mucosal-to-serosal permeation of cephaloridine, but verapamil and p-aminohippuric acid had no significant effect on it. Conclusions: It has been suggested that mechanisms which induce secretory-oriented permeation of orally inactive beta-lactam antibiotics are factors limiting intestinal absorption of such antibiotics. This energy-demanding efflux system was distinct from P-glycoprotein-mediated transport. A free alpha-amino group in the molecule is an important factor for reducing an affinity with the efflux system.