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.
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DOI：
10.1016/j.bmc.2013.05.024
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发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Remmel RP
中科院分区：
文献类型：
--
作者：
Teitelbaum AM;Meissner A;Harding RA;Wong CA;Aldrich CC;Remmel RP
美罗培南是一种广谱肠外β-内酰胺类抗生素，与克拉维辛联合使用，最近在广泛耐药结核病患者中显示出疗效。由于美罗培南的半衰期短且缺乏口服生物利用度，在长期胃肠外治疗不切实际的服务水平低下的国家，有必要开发一种口服疗法用于结核病治疗。为了改善美罗培南的口服吸收，合成了几种具有增加的亲脂性的烷氧基羰基氧基烷基酯前药，并评价了它们在生理水溶液和豚鼠以及人血浆中的稳定性。前药在pH 6.0和7.4的水溶液中的稳定性显著依赖于酯前体，主要降解产物被鉴定为母体化合物美罗培南。然而，在模拟胃肠液（pH 1.2）中，鉴定的主要降解产物为开环美罗培南，前体结构仍然完整，表明胃肠道环境可能会降低美罗培南前药的体内吸收，除非以肠溶包衣制剂给药。此外，大多数水性稳定前药在豚鼠或人血浆中的稳定性较短，这意味着母体美罗培南的快速释放。
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.
影响因子：
4.9
作者：
Stoeckel, K;Hofheinz, W;Blouin, RA
通讯作者：
Blouin, RA
DOI：
10.1016/j.ejpb.2006.05.001
发表时间：
2006-10-01
影响因子：
4.9
作者：
Kakumanu, Vasu Kumar;Arora, Vinod;Bansal, Arvind K.
通讯作者：
Bansal, Arvind K.