Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Key Laboratory of Jiangxi Province for Research on Active Ingredients in Natural Medicines, Bioengineering Research Institute, Yichun University, Yichun, China.
Basic Clin Pharmacol Toxicol. 2019 Aug;125(2):142-151. doi: 10.1111/bcpt.13211. Epub 2019 Mar 25.
High-dose cyclophosphamide (HD-CTX) treatment often leads to severe nephrotoxicity and neurotoxicity, which are mainly caused by one of its metabolites, chloroacetaldehyde (CAA). However, there are no effective antidotes to prevent these side effects. The objective of this study was to evaluate the effect of Wuzhi Capsule (WZC) on the pharmacokinetics of CTX and its metabolites in rats, and the attenuation of CAA induced kidney and brain injuries, which was produced at equimolar with 2-dechloroethylcyclophosphamide. Rats were treated with single- or multiple-dose of WZC when giving HD-CTX, and the plasma concentration of CTX and its metabolites were quantitated by UHPLC-MS/MS Single-dose, not multiple-dose of WZC co-administration (300 mg/kg) significantly reduced C and AUC of DC-CTX by 33.10% and 35.51%, respectively. Biochemical assay suggested oxidative stress was involved in kidney and brain injuries by HD-CTX, which were attenuated by single-dose WZC (300 mg/kg) pre-treatment, with increased glutathione, glutathione peroxidase and superoxide dismutase contents/or activities in both tissues and plasma (P < 0.05). Meanwhile, WZC pre-treatment could also significantly decrease the plasma levels of creatinine, blood urea nitrogen and malondialdehyde (P < 0.05). Additionally, WZC treatment improved the morphology and pathology condition of the kidneys and brains in rats. In conclusion, single-dose WZC co-administration decreased CAA production and exerted protective effect on CTX-induced oxidative stress in kidney and brain, whereas repetitive WZC co-administration with CTX was probably not recommended.
高剂量环磷酰胺（HD-CTX）治疗常导致严重的肾毒性和神经毒性，这主要是由其代谢物之一氯乙醛（CAA）引起的。然而，目前尚无有效的解毒剂来预防这些副作用。本研究旨在评价五酯胶囊（WZC）对大鼠 CTX 及其代谢物药代动力学的影响，以及对等摩尔 2-氯乙基环磷酰胺诱导的肾和脑损伤的抑制作用。在给予 HD-CTX 时，大鼠单次或多次给予 WZC 治疗，并通过 UHPLC-MS/MS 定量检测 CTX 和其代谢物的血浆浓度。单次而非多次 WZC （300mg/kg）联合给药显著降低 C 和 DC-CTX 的 AUC 分别为 33.10%和 35.51%。生化测定提示 HD-CTX 诱导的肾和脑损伤与氧化应激有关，单次 WZC（300mg/kg）预处理可减轻氧化应激，增加组织和血浆中谷胱甘肽、谷胱甘肽过氧化物酶和超氧化物歧化酶的含量/活性（P<0.05）。同时，WZC 预处理还可显著降低血浆肌酐、血尿素氮和丙二醛水平（P<0.05）。此外，WZC 治疗可改善大鼠肾和脑的形态和病理状况。总之，单次 WZC 联合给药可减少 CAA 的产生，并对 CTX 诱导的肾和脑氧化应激发挥保护作用，而重复给予 WZC 与 CTX 联合应用可能并不推荐。
