Improvement of cefpodoxime proxetil oral absorption in rats by an oil-in-water submicron emulsion
Introduction
Cefpodoxime proxetil is an orally absorbed, broad spectrum, third generation cephalosporin ester. This prodrug ester is hydrolyzed in vivo into its active metabolite named cefpodoxime. In humans, the absolute bioavailability of cefpodoxime is about 50% after the administration of cefpodoxime proxetil as a 132 mg tablet (equivalent to 100 mg of cefpodoxime) (Borin, 1991). Previous studies realized in vitro, in rabbit and human duodenal washings (Crauste-Manciet et al., 1997a, Crauste-Manciet et al., 1997b) have shown that cefpodoxime proxetil was hydrolyzed by a cholinesterase prior to its intestinal absorption. These results may explain its incomplete absorption.
Oil-in-water (o/w) submicron emulsion was previously found to be effective in protecting the prodrug from enzymatic attack in rabbit duodenal washings (Crauste-Manciet et al., 1998).
The aim of this work was to study the bioavailability of cefpodoxime in rats after oral administration of cefpodoxime proxetil in different formulation which are: o/w coarse emulsion, o/w submicron emulsion, suspension and hydro-alcoholic solution.
Section snippets
Materials
Cefpodoxime proxetil was kindly provided by Roussel Uclaf (Romainville, France). Medium-chain-triglycerides (MCT) of caprylic and capric acids (Miglyol 812N®) were provided by Condea (Witten, Germany). Blends of mono-(50%), di-(40%) and triesters (8%) of caprylic and capric acids (Inwitor 742®) were supplied from Hüls (Marl, Germany). Soybean lecithin (Lipoı̈d S40®) was provided by Lipoı̈dKG (Ludwigshafen, Germany). Polysorbate 80 (Montanox 80®) was purchased from Seppic (Paris, France).
Results
Pharmacokinetic parameters obtained after intra-aortic injection of cefpodoxime (n=9) show a constant of elimination ke of 16.5×10−3±2.6×10−3 min−1, an elimination half-time t1/2 of 42±6.6 min, a MRT of 1.05±0.27 h, a clearance of 0.46±0.03 ml/min, a C0 of 111±11 μg/ml and a AUC0→∞ of 4383±317 μg min/ml. Pharmacokinetic parameters obtained after oral administration of cefpodoxime proxetil are listed in Table 3.
The values of Cmax of suspension, coarse emulsion and submicron emulsion are equivalent. Cmax
Discussion
Lipophile prodrugs such as cefpodoxime proxetil are generally incompletely absorbed. This is essentially due to a partial solubilization of the drug in aqueous phase in the intestinal lumen and to enzymatic hydrolysis prior to absorption (Crauste-Manciet et al., 1997a). We found that the submicron emulsion shows the greater absolute bioavailability, which is even equivalent to the parenteral solution value.
The pharmacokinetic parameters of cefpodoxime calculated from the parenteral solution
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