Investigation on physicochemical and biological differences of cefpodoxime proxetil enantiomers

Kakumanu, Vasu Kumar; Arora, Vinod; Bansal, Arvind K.

doi:10.1016/j.ejpb.2006.05.001

Cited by 10 publications

(8 citation statements)

References 6 publications

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“…Kakumanu et al found that the R isomer of cefpodoxime proxetil was metabolized more quickly than the S isomer in rat intestinal homogenates, confirming stereoselective hydrolysis of proxetil esters. 34 …”

Section: Resultsmentioning

confidence: 99%

Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

Teitelbaum

Meißner

Harding

et al. 2013

Bioorganic & Medicinal Chemistry

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Meropenem, a broad-spectrum parenteral β-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem’s short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem.

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Section: Resultsmentioning

confidence: 99%

Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

Teitelbaum

Meißner

Harding

et al. 2013

Bioorganic & Medicinal Chemistry

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“…Chiral separations are important, especially in the pharmaceutical industry, as enantiomers often possess different health benefits [1]. The analysis and preparation of a pure enantiomer usually involve its separation from the antipode.…”

Section: Introductionmentioning

confidence: 99%

Enantiomeric Separation and Quantitation of Tenofovir Disoproxil Fumarate Using Amylose-Based Chiral Stationary Phases by High-Performance Liquid Chromatography

Heydari¹,

Shamsipur²

2015

Acta Chromatographica

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Summary.A rapid high-performance liquid chromatography (HPLC) method for chiral purity determination of tenofovir disoproxil fumarate in raw material and pharmaceutical formulations was developed. The (S)-enantiomer appears to be as an impurity and pharmacologically inactive. The effects of various stationary phases, mobile phase composition, and column temperature on enantiomeric separation of tenofovir disoproxil were investigated and optimized. Chromatography resolution of tenofovir disoproxil enantiomers was performed on NUCLEOCEL ALPHA-RP S column (250 × 4.6 mm i.d., 5 µm). The elution was achieved by using 95:5% (v/v) methanol-acetonitrile, containing 0.1% triethylamine at a flow rate of 0.8 mL min −1 . The ultraviolet (UV) detector was set at 260 nm. Calibration curves were linear in the range of 1-100 µg mL −1 and 0.2-20 µg mL −1 for (R)-tenofovir disoproxil and (S)-enantiomer, respectively. Limits of detection and quantitation for (S)-enantiomer were 0.06 and 0.2 µg mL −1 . The run time of analysis was less than 7.0 min. The proposed method was used successfully for separation and quantification of tenofovir disoproxil enantiomers in raw material and pharmaceutical formulations.

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“…The reasons for low oral bioavailability of cefpodoxime proxetil are mainly attributed to low water solubility (400 μg/ ml), typical gelation behavior of cefpodoxime proxetil particularly in acidic environments (6)(7)(8), and pre-absorption luminal metabolism of its ester side chain by digestive enzymes cholinesterases present in the intestinal lumen into CA (9).…”

Section: Introductionmentioning

confidence: 99%

“…Although cefpodoxime proxetil, the prodrug ester, is hydrolyzed in vivo to its active metabolite, cefpodoxime is designed to improve the permeability and thus bioavailability of the parent molecule cefpodoxime acid (CA); it still has only 50% oral bioavailability when administered orally as a 132-mg tablet, equivalent to 100 mg of cefpodoxime in humans (6). Cefpodoxime proxetil is a non-crystalline, slightly basic compound and is absorbed from the gastrointestinal tract after oral administration and hydrolyzed to its parent moiety CA by nonspecific esterases in the intestinal wall/plasma (7).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of Bioavailability of Cefpodoxime Proxetil Using Different Polymeric Microparticles

2010

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Abstract. Poorly water-soluble drugs such as cefpodoxime proxetil (400 μg/ml) offer a challenging problem in drug formulation as poor solubility is generally associated with poor dissolution characteristics and thus poor oral bioavailability. According to these characteristics, preparation of cefpodoxime proxetil microparticle has been achieved using high-speed homogenization. Polymers (methylcellulose, sodium alginate, and chitosan) were precipitated on the surface of cefpodoxime proxetil using sodium citrate and calcium chloride as salting-out agents. The pure drug and the prepared microparticles with different concentrations of polymer (0.05-1.0%) were characterized in terms of solubility, drug content, particle size, thermal behavior (differential scanning calorimeter), surface morphology (scanning electron microscopy), in vitro drug release, and stability studies. The in vivo performance was assessed by pharmacokinetic study. The dissolution studies demonstrate a marked increase in the dissolution rate in comparison with pure drug. The considerable improvement in the dissolution rate of cefpodoxime proxetil from optimized microparticle was attributed to the wetting effect of polymers, altered surface morphology, and micronization of drug particles. The optimized microparticles exhibited excellent stability on storage at accelerated condition. The in vivo studies revealed that the optimized formulations provided improved pharmacokinetic parameter in rats as compared with pure drug. The particle size of drug was drastically reduced during formulation process of microparticles.

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Investigation on physicochemical and biological differences of cefpodoxime proxetil enantiomers

Cited by 10 publications

References 6 publications

Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

Enantiomeric Separation and Quantitation of Tenofovir Disoproxil Fumarate Using Amylose-Based Chiral Stationary Phases by High-Performance Liquid Chromatography

Enhancement of Bioavailability of Cefpodoxime Proxetil Using Different Polymeric Microparticles

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