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目的:观察长期应用不同剂量关木通提取物诱导的大鼠肾毒性的变化,并分析其与马兜铃酸A血药浓度的关系。方法:SD大鼠随机分为5组:正常对照组,低盐对照组,低、中、高剂量组,于给药后第4和6周观察大鼠肾功能和肾组织形态学的变化。马兜铃酸A血药浓度采用液质联用(LC/MS/MS)法测定。结果:与低盐对照组相比,药后第2周低、中、高剂量组尿量增多,第4周时尿量减少,低、中剂量组其他各指标无明显变化,高剂量组尿蛋白和尿素氮(BUN)升高;药后第6周时,高剂量组尿量进一步减少,尿蛋白、肌酐(Crea)和BUN明显升高;病理表现为肾小管细胞空泡变性及小动脉和肾间质病变;高剂量组各种变化较低、中剂量组更为明显。各项检测指标在2个对照组间差异无统计学意义。药后6周血浆中马兜铃酸A浓度极低。结论:大鼠长期应用关木通提取物可导致肾脏功能和组织学病变,且病变程度与用药时间和剂量有明显的相关性,而与马兜铃酸A血药浓度可能无关。
OBJECTIVE: To observe the changes of nephrotoxicity induced by long-term application of different doses of Guanmutong extract, and to analyze the relationship between it and the plasma concentration of aristolochic acid A. Methods: SD rats were randomly divided into 5 groups: normal control group, low-salt control group, low-, medium-, and high-dose groups. The changes of renal function and renal histology were observed at 4 and 6 weeks after administration. The plasma concentration of aristolochic acid A was determined by liquid chromatography coupled with mass spectrometry (LC/MS/MS). Results: Compared with the low-salt control group, the urine output of the low, middle, and high dose groups increased at the second week after drug administration, and the urine volume decreased at the fourth week. There was no significant change in other indexes of the low and middle dose groups. Protein and blood urea nitrogen (BUN) increased; at week 6 after drug administration, urine output was further reduced in the high-dose group, urinary protein, creatine (Crea), and BUN were significantly elevated; pathological findings were vacuolar degeneration of tubular cells and arterioles And renal interstitial lesions; high dose group, a variety of changes in the lower dose group is more obvious. There was no significant difference in the detection indicators between the two control groups. The concentration of aristolochic acid A in plasma was extremely low at 6 weeks after drug administration. Conclusion: The long-term application of Guan Mu Tong extract in rats can lead to renal functional and histological lesions, and the degree of the lesions has a significant correlation with the time and dose of medication, but may not be related to the plasma concentration of aristolochic acid A.