Guo Chenxue, Xi Lin, Qu Xingyi, Huang Zhiwei, Li Size, Li Wanzhen, Liu Xiaofen, Zhang Jing
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, 200040, China.
Sci Rep. 2025 May 10;15(1):16299. doi: 10.1038/s41598-025-96407-7.
Nephrotoxicity has seriously affected the clinical application of colistin methanesulphonate (CMS). Colistin B methanesulphonate (CMS-E2) is a novel polymyxin developed and aimed to have lower nephrotoxicity. This study aimed to investigate the relationships between pharmacokinetics (PK) and nephrotoxicity of CMS and CMS-E2 and compare the toxicity of the two drugs in rats. Rats were treated intraperitoneally with a single dose of saline, CMS [10, 20 mg/kg of colistin base activity (CBA)], and CMS-E2 (20, 40 mg/kg CBA). An LC-MS/MS method was developed to determine plasma and renal tissue concentrations of CMS/CMS-E2 and colistin/colistin B. The severity of renal injuries was examined both biochemically and histologically. The PK-toxicodynamic (TD) model was evaluated to characterize the PK of CMS/CMS-E2 and colistin/colistin B in plasma as well as its relationship with nephrotoxicity. Creatinine (CR) and blood urea nitrogen (BUN) profiles were described using an indirect link PK-TD model, with linear-effect relationship. Both the slope between colistin or colistin B concentrations in the effect compartment and CR, BUN was significantly lower for CMS-E2 compared with CMS (CR: P = 0.027, BUN: P = 0.043). The concentrations of colistin and colistin B in kidneys were correlated with CR, BUN values, and histologic examination scores. The regression coefficient of CMS-E2 between the colistin B concentrations in renal tissues and CR, BUN values were lower, as well (CR: P = 0.003, BUN: P = 0.001). The renal injuries induced by CMS and CMS-E2 lagged behind the change of plasma colistin or colistin B concentrations and correlated to those in kidneys. CMS-E2 showed significantly lower nephrotoxicity compared to CMS in vivo.
肾毒性严重影响了多粘菌素甲磺酸钠（CMS）的临床应用。多粘菌素B甲磺酸钠（CMS-E2）是一种新开发的多粘菌素，旨在降低肾毒性。本研究旨在探讨CMS和CMS-E2的药代动力学（PK）与肾毒性之间的关系，并比较两种药物在大鼠体内的毒性。将大鼠腹腔注射单剂量的生理盐水、CMS[10、20mg/kg的多粘菌素碱活性（CBA）]和CMS-E2（20、40mg/kg CBA）。建立了一种液相色谱-串联质谱（LC-MS/MS）方法来测定血浆和肾组织中CMS/CMS-E2以及多粘菌素/多粘菌素B的浓度。通过生化和组织学方法检查肾损伤的严重程度。评估PK-毒效动力学（TD）模型以表征CMS/CMS-E2和多粘菌素/多粘菌素B在血浆中的PK及其与肾毒性的关系。使用间接联系的PK-TD模型描述肌酐（CR）和血尿素氮（BUN）曲线，具有线性效应关系。与CMS相比，CMS-E2在效应室中的多粘菌素或多粘菌素B浓度与CR、BUN之间的斜率均显著更低（CR：P=0.027，BUN：P=0.043）。肾脏中多粘菌素和多粘菌素B的浓度与CR、BUN值以及组织学检查评分相关。肾组织中多粘菌素B浓度与CR、BUN值之间CMS-E2的回归系数也更低（CR：P=0.003，BUN：P=0.001）。CMS和CMS-E2诱导的肾损伤滞后于血浆多粘菌素或多粘菌素B浓度的变化，并与肾脏中的变化相关。在体内，CMS-E2的肾毒性明显低于CMS。
