Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, United States.
Bioorg Med Chem. 2013 Sep 1;21(17):5605-17. doi: 10.1016/j.bmc.2013.05.024. Epub 2013 May 24.
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.
美罗培南是一种广谱的注射用β-内酰胺类抗生素，与克拉维酸联合使用时，对广泛耐药结核病患者显示出疗效。由于美罗培南半衰期短且口服生物利用度低，因此需要开发一种口服治疗药物，用于在无法提供慢性注射治疗的资源匮乏国家进行结核病治疗。为了提高美罗培南的口服吸收，合成了几种亲脂性增加的烷氧基羰氧基烷基酯前药，并评估了它们在生理水溶液以及豚鼠和人血浆中的稳定性。前药在 pH 值为 6.0 和 7.4 的水溶液中的稳定性显著依赖于酯基，主要降解产物被鉴定为母体化合物美罗培南。然而，在模拟胃肠道液（pH 1.2）中，主要降解产物是开环的美罗培南，而 promoiety 仍然完整，这表明胃肠道环境可能会降低美罗培南前药在体内的吸收，除非以肠溶包衣制剂给药。此外，在豚鼠或人血浆中最稳定的前药的稳定性也很短，这意味着母体美罗培南会迅速释放。
