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


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 of 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.
Saitoh
H
H
Department of Pharmacy, Hokkaido University Hospital, School of Medicine, Hokkaido University, Sapporo, Japan.
Fujisaki
H
H
Aungst
B J
BJ
Miyazaki
K
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004734:Energy Metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000502:physiology; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D014528:Uricosuric Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology; D047090:beta-Lactams; D010130:p-Aminohippuric Acid / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D002121:Calcium Channel Blockers; D014528:Uricosuric Agents; D047090:beta-Lactams; D014700:Verapamil; D011339:Probenecid; D010130:p-Aminohippuric Acid