Faísca Francisco, Petrovski Željko, Grilo Inês, Lima Sofia A C, Santos Miguel M, Branco Luis C
LAQV-REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, NOVA University of Lisbon, 2819-516 Caparica, Portugal.
UCIBIO-Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal.
Pharmaceutics. 2024 Oct 2;16(10):1291. doi: 10.3390/pharmaceutics16101291.
Low oral bioavailability is a common feature in most drugs, including antibiotics, due to low solubility in physiological media and inadequate cell permeability, which may limit their efficacy or restrict their administration in a clinical setting. Cefuroxime is usually administered in its prodrug form, cefuroxime axetil. However, its preparation requires further reaction steps and additional metabolic pathways to be converted into its active form. The combination of Active Pharmaceutical Ingredients (APIs) with biocompatible organic molecules as salts is a viable and documented method to improve the solubility and permeability of a drug. Herein, the preparations of five organic salts of cefuroxime as an anion with enhanced physicochemical characteristics have been reported. These were prepared via buffer-assisted neutralization methodology with pyridinium and imidazolium cations in quantitative yields and presented as solids at room temperature. Cell viability studies on 3T3 cells showed that only the cefuroxime salts combined with longer alkyl chain cations possess higher cytotoxicity than the original drug, and while most salts lost in vitro antibacterial activity against and , one compound, [PyCPy][CFX], retained the activity. Cefuroxime organic salts have a water solubility 8-to-200-times greater than the original drug at 37 °C. The most soluble compounds have a very low octanol-water partition, similar to cefuroxime, while more lipophilic salts partition predominantly to the organic phase.
由于在生理介质中的低溶解度和细胞通透性不足，低口服生物利用度是包括抗生素在内的大多数药物的共同特征，这可能会限制它们的疗效或在临床环境中的给药方式。头孢呋辛通常以其前药形式头孢呋辛酯给药。然而，其制备需要进一步的反应步骤和额外的代谢途径才能转化为其活性形式。将活性药物成分（API）与生物相容性有机分子作为盐进行组合是一种可行且有文献记载的提高药物溶解度和通透性的方法。在此，已报道了五种以头孢呋辛为阴离子且具有增强物理化学特性的有机盐的制备方法。这些盐是通过缓冲辅助中和方法与吡啶鎓和咪唑鎓阳离子定量制备的，在室温下呈固体状态。对3T3细胞的细胞活力研究表明，只有与较长烷基链阳离子结合的头孢呋辛盐比原药具有更高的细胞毒性，并且虽然大多数盐对[具体细菌名称1]和[具体细菌名称2]失去了体外抗菌活性，但一种化合物[PyCPy][CFX]保留了活性。头孢呋辛有机盐在37℃时的水溶性比原药高8至200倍。最易溶的化合物具有非常低的正辛醇 - 水分配系数，与头孢呋辛相似，而亲脂性更强的盐主要分配到有机相中。
