Abstract
The effect of different metal ions on the intestinal transport and the antibacterial activity of cefadroxil [(6R,7R)-7-{[(2R)-2-amino-2-(4-hydroxyphenyl)acetyl]amino}-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid] was investigated. The [14C]Gly-Sar uptake via PEPT1 was inhibited by Zn2+ and Cu2+ treatment in a concentration-dependent manner (Ki values 107 ± 23 and 19 ± 5 µM, respectively). Kinetic analysis showed that the Kt of Gly-Sar uptake was increased 2-fold in the presence of zinc sulphate (150 µM) whereas the Vmax value were not affected suggesting that zinc ions inhibited Gly-Sar uptake by PEPT1 in a competitively manner. Ni2+ exhibited moderate inhibitory effect, whereas Co2+, Mg2+, Al3+ ions showed no inhibitory effect on Gly-Sar uptake via PEPT1. Subsequently, we examined the effect of Zn2+ and Al3+ ions on the transepithelial transport of cefadroxil across Caco-2 cells cultured on permeable supports. The results showed that zinc ions inhibited the transepithelial flux of cefadroxil at Caco-2 cell monolayers while Al3+ ions had no effect. The interaction of cephalosporins with the metal ions could suggest negative effects of some metal ions on the clinical aspects of small intestinal peptide and drug transport. Finally, the effect of Zn2+, Cu2+ and Al3+ ions on the antibacterial activity of cefadroxil was tested. It was found that there is no significant difference between the activity of cefadroxil and the cefadroxil metal ion complexes studied against the investigated sensitive bacterial species.
Highlights
Cefadroxil is a semi-synthetic first generation cephalosporin which has been introduced into clinical practice and recommended for oral use
We examined the effect of different metal ions on the transport of Gly-Sar and cefadroxil in Caco-2 cells as well as their effect on the antimicrobial activity of cefadroxil
Zn2+ ions inhibit the intestinal transport of cefadroxil by forming strong complexes with cefadroxil
Summary
Cefadroxil is a semi-synthetic first generation cephalosporin which has been introduced into clinical practice and recommended for oral use. Most of the dipeptides and tripeptides are hydrolyzed by cytosolic peptidases and are released as free amino acids into circulation [6] Due to their broad substrate specificity, PEPT1 and PEPT2 can accept several peptide-like drugs structurally related to small peptides such as oral β-lactam antibiotics, the anticancer agent bestatin and the antiviral drug val-acyclovir [4,7,8]. It has been well established that the good oral availability of certain β-lactams, in particular of the cephalosporins, is a consequence of their ability to use the intestinal peptide transporter for the uptake into circulation [9,10] Because of this characteristic, cefadroxil has been used in expression cloning to isolate the cDNA clones that encode PEPT1 and PEPT2 [11]. We examined the effect of different metal ions on the transport of Gly-Sar and cefadroxil in Caco-2 cells as well as their effect on the antimicrobial activity of cefadroxil
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