Improvement of cefpodoxime proxetil oral absorption in rats by an oil-in-water submicron emulsion

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Abstract

Absolute bioavailability of cefpodoxime proxetil is both limited by its low solubility in aqueous solution and its intraluminal hydrolysis. The oil-in-water submicron emulsion was proven to be effective in protecting the prodrug from the enzymatic attack in rabbit intestinal washings. The aim of the study was to perform a pharmacokinetic study in conscious rats to confirm o/w submicron superiority in comparison to other oral formulations (hydro-alcoholic solution, suspension and coarse emulsion).

The pharmacokinetic study was performed in conscious rats implanted with permanent aortic catheters. A parenteral solution of cefpodoxime was injected via this catheter, and oral formulations were administered orally. The cefpodoxime plasma level was performed by a HPLC validated method. The pharmacokinetic parameters, t1/2, Cmax, tmax, AUC and absolute bioavailability (F) were determined with a non-compartmental analysis. The results show a significant increase of F for submicron emulsion (97.4%) between the other oral formulations. No significant difference of F was found between the other oral formulations, even with the coarse o/w emulsion.

The o/w submicron emulsion made the enhancement of the absolute bioavailability of cefpodoxime proxetil possible. This benefit could be explained by the low droplet size of the submicron emulsion which improve the absorption process of the prodrug.

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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      These data support a developmental dependence in the disposition of cefpodoxime in pediatric patients following the administration of the prodrug ester, cefpodoxime proxetil. Nicolaos et al. [151] performed a pharmacokinetic study in conscious rats to confirm the oil-in-water submicron superiority in comparison to other oral formulations (hydroalcoholic solution, suspension and coarse emulsion). Absolute bioavailability of cefpodoxime proxetil is both limited by its low solubility in aqueous solution and its intraluminal hydrolysis.

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