B Bretschneider1, M Brandsch, R Neubert. 1. Department of Pharmacy, Institute of Pharmaceutics and Biopharmaceutics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Abstract
PURPOSE: This study on the intestinal transport of beta-lactam antibiotics was undertaken to investigate the correlation between cellular transport parameters and the bioavailability. METHODS: Transport of 23 beta-lactam antibiotics was characterized by measuring their ability to inhibit the uptake of glycylsarcosine into Caco-2 cells, their uptake into the cells and their total flux across the cell monolayers. RESULTS: Ceftibuten and cyclacillin were recognized by PEPT1 with affinity constants comparable to those of natural dipeptides (K(i) = 0.3 and 0.5 mM, respectively). Cefadroxil, cefamandole, cephradine, cefaclor, cefuroxime-axetil, cefixime, cephalotin, cephalexin and ampicillin also interacted with PEPTI (K(i) = 7-14 mM). In contrast, cefapirin, cefodizime, cefuroxime, cefmetazole, ceftazidime, benzyl-penicillin, ceftriaxone, cefpirome, cefotaxime, cefepime, cephaloridine and cefsulodin displayed no affinity to the transport system (K(i) > 20 mM). The uptake into the cells and the transepithelial flux was highest for those beta-lactam antibiotics, which showed the strongest inhibition of [14C]Gly-Sar transport (p < 0.0001). Exceptions were cefuroximaxetil and cephalotin. CONCLUSIONS: The probability of oral bioavailability for beta-lactam antibiotics is mainly determined by their affinity to PEPTI. A threshold K(i) value of 14 mM with respect to Gly-Sar uptake is required.
PURPOSE: This study on the intestinal transport of beta-lactam antibiotics was undertaken to investigate the correlation between cellular transport parameters and the bioavailability. METHODS: Transport of 23 beta-lactam antibiotics was characterized by measuring their ability to inhibit the uptake of glycylsarcosine into Caco-2 cells, their uptake into the cells and their total flux across the cell monolayers. RESULTS:Ceftibuten and cyclacillin were recognized by PEPT1 with affinity constants comparable to those of natural dipeptides (K(i) = 0.3 and 0.5 mM, respectively). Cefadroxil, cefamandole, cephradine, cefaclor, cefuroxime-axetil, cefixime, cephalotin, cephalexin and ampicillin also interacted with PEPTI (K(i) = 7-14 mM). In contrast, cefapirin, cefodizime, cefuroxime, cefmetazole, ceftazidime, benzyl-penicillin, ceftriaxone, cefpirome, cefotaxime, cefepime, cephaloridine and cefsulodin displayed no affinity to the transport system (K(i) > 20 mM). The uptake into the cells and the transepithelial flux was highest for those beta-lactam antibiotics, which showed the strongest inhibition of [14C]Gly-Sar transport (p < 0.0001). Exceptions were cefuroximaxetil and cephalotin. CONCLUSIONS: The probability of oral bioavailability for beta-lactam antibiotics is mainly determined by their affinity to PEPTI. A threshold K(i) value of 14 mM with respect to Gly-Sar uptake is required.
Authors: M Brandsch; S Ramamoorthy; N Marczin; J D Catravas; J W Leibach; V Ganapathy; F H Leibach Journal: J Clin Invest Date: 1995-07 Impact factor: 14.808
Authors: Hugues Chanteux; Isabelle Paternotte; Marie-Paule Mingeot-Leclercq; Robert Brasseur; E Sonveaux; Paul M Tulkens Journal: Pharm Res Date: 2003-04 Impact factor: 4.200