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.
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, United States.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Teitelbaum
authors.forename: Anja
authors.initials: A
authors.lastname: Meissner
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Harding
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wong
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
authors.forename: Rory P
authors.initials: RP
authors.lastname: Remmel
mesh_terms: D000818:Animals; D004355:Drug Stability; D006168:Guinea Pigs; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000077731:Meropenem; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013845:Thienamycins / Q000097:blood / Q000737:chemistry* / Q000627:therapeutic use; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy; D014867:Water / Q000737:chemistry
chemical_list: D011355:Prodrugs; D013845:Thienamycins; D014867:Water; D000077731:Meropenem
keywords: Aqueous stability; Meropenem; XDR-TB; β-Lactam prodrugs