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

Aaron M Teitelbaum1, Anja Meissner, Ryan A Harding

  • 1Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, United States.

Bioorganic & Medicinal Chemistry
|July 13, 2013
PubMed

Insights

Developing oral meropenem prodrugs for tuberculosis (TB) treatment shows promise. However, stability in simulated gastrointestinal fluid suggests potential absorption issues, requiring formulation adjustments for effective oral delivery.

Area of Science:

  • Pharmacology
  • Medicinal Chemistry
  • Infectious Diseases

Background:

  • Meropenem is a broad-spectrum antibiotic effective against extensively drug-resistant tuberculosis (TB).
  • Meropenem's short half-life and poor oral bioavailability limit its use in resource-limited settings.
  • Oral meropenem therapy is needed for practical TB treatment.

Purpose of the Study:

  • To synthesize and evaluate novel meropenem prodrugs for improved oral absorption.
  • To assess the stability of these prodrugs in various physiological conditions.

Main Methods:

  • Synthesis of alkyloxycarbonyloxyalkyl ester prodrugs of meropenem.
  • Evaluation of prodrug stability in aqueous solutions (pH 6.0, 7.4) and simulated gastrointestinal fluid (pH 1.2).
  • Assessment of prodrug stability in guinea pig and human plasma.

Main Results:

  • Prodrug stability in aqueous solutions depended on the promoiety, with meropenem as the main degradation product.
  • In simulated gastric fluid, ring-opened meropenem was the major product, indicating potential absorption challenges.
  • Prodrugs showed short stability in plasma, suggesting rapid release of meropenem.

Conclusions:

  • Meropenem prodrugs demonstrate potential for oral delivery but require formulation strategies, such as enteric coating, to overcome gastrointestinal instability.
  • Further research is needed to optimize prodrug design for effective in vivo absorption and sustained release.
Keywords:
Aqueous stabilityMeropenemXDR-TBβ-Lactam prodrugs

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