Modification of cefixime bioavailability by nifedipine in humans: involvement of the dipeptide carrier system

Abstract

We studied the action of nifedipine on the bioavailablity of cefixime, a molecule absorbed via the gut wall dipeptide carrier system in the rat, and on the bioavailability of D-xylose, which is absorbed via a pH (and Na+-)-dependent transporter. Each compound was administered alone or in combination with 20 mg of nifedipine to eight healthy male volunteers. Nifedipine significantly increased the absorption rate of cefixime (20.7 + 4.3 versus 16 ± 3.5 mg/h in the absence of nifedipine). The absolute bioavailability of cefixime alone was 31% ± 6% compared with 53% ± 1% (P < 0.01) in the presence of nifedipine. The observed peak concentrations in serum were significantly different (2.5 ± 0.3 mg/liter without nifedipine and 3.7 ± 1.1 mg/liter with nifedipine; P < 0.02). In contrast, nifedipine induced no significant differences in the pharmacokinetic profile of xylose following oral administration. We conclude that (i) cefixime is absorbed in humans by an apparently active process which can be enhanced by a calcium channel blocker, in this case, nifedipine; and (ii) nifedipine does not modify the activity of the pentose transporter.Cefixime was the first broad-spectrum oral cephalosporin to be marketed. It is characterized by the presence of two nonesterified carboxylic functions and by its stability to acid hydrolysis, which is due to the presence of a vinyl group on the cephem nucleus (12).Intestinal absorption of cefixime in the rat occurs by an active mechanism involving a pH-dependent dipeptide transporter similar to that of amoxicillin (14-16). The transporter is saturable and is inhibited by glycyl-L-proline and glycyl-L-glycine. The same mechanism has been hypothesized by Lowther et al. (9), who studied human brush border membrane vesicles. Recent studies in healthy volunteers have shown that nifedipine increases both the absorption rate and the bioavailability of amoxicillin without modifying its distribution or elimination (18). This may be explained by a direct stimulation of drug uptake, as the decrease in intracellular calcium levels increases transmembrane Na+-H+ ion exchanges, resulting in increased intraenterocyte pH, which in turn increases the activity of the transporter (18).Since animal studies have shown that the transport systems for cefixime and amoxicillin are the same (15), we assessed the absorption rate of cefixime and the influence of nifedipine on the intestinal absorption kinetics and bioavailability of cefixime in healthy volunteers.In order to identify the specificity of the interaction, we studied the action of nifedipine on the uptake of a pentose (D-xylose), which, when administered at the dose of 5 g, is absorbed via a pH (and Na+-)-dependent transporter (4,8 Protocol. The protocol was divided into two phases, cefixime-nifedipine and D-xylose-nifedipine, and the same subjects were used in both.(i) Phase 1: cefixime-nifedipine. The protocol for phase 1 was similar to that used by Westphal et al. (18) and involved oral administration followed by i.v. administration. In the study of ...

PEPT1-Mediated Cefixime Uptake into Human Intestinal Epithelial Cells Is Increased by Ca 2+ Channel Blockers

“…The interesting clinical observation that the coadministration of cefixime with Ca 2ϩ channel blockers can increase the (14) suggested that there are mechanisms that can increase the level of cefixime uptake by PEPT1. It has been shown that this increase in transport by nifedipine also applies to the PEPT1 substrates cephalexin and amoxicillin (4,5,45), zwitterionic compounds that already show high intestinal absorption rates in vivo.…”

Synthesis and Antibacterial Activity of Cefixime Metal Complexes

“…It is highly b-lactamase stable and, as a result, many organisms resistant to penicillin and some cephalosporins are susceptible to cefixime. As a third generation cephalosporin is more resistant to hydrolysis by the b-lactamases produced by gram-negative bacteria than first-generation cephalosporins, it is characterized by the presence of two nonesterified carboxylic functions and by its stability to acid hydrolysis, which is due to the presence of a vinyl group on the cephen nucleus [1][2][3]. The structural formula for cefixime is shown in Figure 1.…”

Transfer of Plasmid-Mediated CTX-M-9 from Salmonella enterica Serotype Virchow to Enterobacteriaceae in Human Flora-Associated Rats Treated with Cefixime

“…However, the Ͼ2-log 10 decrease in Enterobacteriaceae counts during cefixime treatment in our study demonstrated that the antibiotic was present in the digestive tract of our rats. According to the pharmacokinetic study of cefixime in rats, the bioavailability of cefixime was estimated at 30% (data not shown) and comparable to the rat and human data previously described (18,39), so the part excreted in the gastrointestinal tract may be considered approximately 70%. Based on these observations, we hypothesized that cefixime was hydrolyzed during transit by the ␤-lactamases-producing strains of anaerobic endogenous flora as previously described (11,26,42).…”