The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in rats
Abstract 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) an...
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Nature Portfolio
2025-05-01
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| author | Chenxue Guo Lin Xi Xingyi Qu Zhiwei Huang Size Li Wanzhen Li Xiaofen Liu Jing Zhang |
| author_facet | Chenxue Guo Lin Xi Xingyi Qu Zhiwei Huang Size Li Wanzhen Li Xiaofen Liu Jing Zhang |
| author_sort | Chenxue Guo |
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| description | Abstract 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. |
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| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-300efdcffc5c486687149d2aa5cb4ebd2025-08-20T02:15:15ZengNature PortfolioScientific Reports2045-23222025-05-0115111410.1038/s41598-025-96407-7The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in ratsChenxue Guo0Lin Xi1Xingyi Qu2Zhiwei Huang3Size Li4Wanzhen Li5Xiaofen Liu6Jing Zhang7Institute of Antibiotics, Huashan Hospital, Fudan UniversityInstitute of Antibiotics, Huashan Hospital, Fudan UniversityInstitute of Antibiotics, Huashan Hospital, Fudan UniversityInstitute of Antibiotics, Huashan Hospital, Fudan UniversityInstitute of Antibiotics, Huashan Hospital, Fudan UniversityInstitute of Antibiotics, Huashan Hospital, Fudan UniversityInstitute of Antibiotics, Huashan Hospital, Fudan UniversityInstitute of Antibiotics, Huashan Hospital, Fudan UniversityAbstract 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.https://doi.org/10.1038/s41598-025-96407-7ColistinColistin methanesulphonate (CMS)Colistin BPolymyxinsPharmacokinetic-toxicodynamicNephrotoxicity |
| spellingShingle | Chenxue Guo Lin Xi Xingyi Qu Zhiwei Huang Size Li Wanzhen Li Xiaofen Liu Jing Zhang The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in rats Scientific Reports Colistin Colistin methanesulphonate (CMS) Colistin B Polymyxins Pharmacokinetic-toxicodynamic Nephrotoxicity |
| title | The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in rats |
| title_full | The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in rats |
| title_fullStr | The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in rats |
| title_full_unstemmed | The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in rats |
| title_short | The pharmacokinetic-nephrotoxicity relationships of CMS and CMS-E2 from the perspective of plasma and kidney drug concentrations in rats |
| title_sort | pharmacokinetic nephrotoxicity relationships of cms and cms e2 from the perspective of plasma and kidney drug concentrations in rats |
| topic | Colistin Colistin methanesulphonate (CMS) Colistin B Polymyxins Pharmacokinetic-toxicodynamic Nephrotoxicity |
| url | https://doi.org/10.1038/s41598-025-96407-7 |
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