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

Aaron M. Teitelbaum, Anja Meissner, Ryan A. Harding, Christopher A. Wong, Courtney Aldrich, Rory P Remmel

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5605-5617
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number17
DOIs
StatePublished - Sep 1 2013

Fingerprint

meropenem
Multidrug-Resistant Tuberculosis
Plasma stability
Prodrugs
Pharmaceutical Preparations
Plasma (human)
Guinea Pigs
Esters
Extensively Drug-Resistant Tuberculosis
Lactams
Degradation
Clavulanic Acid
Biological Availability
Half-Life
Therapeutics

Keywords

  • Aqueous stability
  • Meropenem
  • XDR-TB
  • β-Lactam prodrugs

Cite this

Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis. / Teitelbaum, Aaron M.; Meissner, Anja; Harding, Ryan A.; Wong, Christopher A.; Aldrich, Courtney; Remmel, Rory P.

In: Bioorganic and Medicinal Chemistry, Vol. 21, No. 17, 01.09.2013, p. 5605-5617.

Research output: Contribution to journalArticle

Teitelbaum, Aaron M. ; Meissner, Anja ; Harding, Ryan A. ; Wong, Christopher A. ; Aldrich, Courtney ; Remmel, Rory P. / Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis. In: Bioorganic and Medicinal Chemistry. 2013 ; Vol. 21, No. 17. pp. 5605-5617.
@article{4c93b31dfe9c4957bdf008d782d6099b,
title = "Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis",
abstract = "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.",
keywords = "Aqueous stability, Meropenem, XDR-TB, β-Lactam prodrugs",
author = "Teitelbaum, {Aaron M.} and Anja Meissner and Harding, {Ryan A.} and Wong, {Christopher A.} and Courtney Aldrich and Remmel, {Rory P}",
year = "2013",
month = "9",
day = "1",
doi = "10.1016/j.bmc.2013.05.024",
language = "English (US)",
volume = "21",
pages = "5605--5617",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "17",

}

TY - JOUR

T1 - Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

AU - Teitelbaum, Aaron M.

AU - Meissner, Anja

AU - Harding, Ryan A.

AU - Wong, Christopher A.

AU - Aldrich, Courtney

AU - Remmel, Rory P

PY - 2013/9/1

Y1 - 2013/9/1

N2 - 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.

AB - 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.

KW - Aqueous stability

KW - Meropenem

KW - XDR-TB

KW - β-Lactam prodrugs

UR - http://www.scopus.com/inward/record.url?scp=84881371260&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881371260&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2013.05.024

DO - 10.1016/j.bmc.2013.05.024

M3 - Article

C2 - 23845282

AN - SCOPUS:84881371260

VL - 21

SP - 5605

EP - 5617

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 17

ER -