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目的采用重复多次给药毒性研究的三种剂量对马兜铃酸Ⅰ进行毒代动力学的初步研究,了解在毒性实验条件下马兜铃酸Ⅰ所达到的全身暴露与毒性之间的内在联系,为安全性评价和毒性机制的研究提供参考资料。方法分别灌胃给予大鼠马兜铃酸Ⅰ30、15、5 mg.kg-1,每天1次,连续14 d,测定不同时间点的血浆药物浓度,用DAS药动学程序对血药浓度-时间数据进行拟合并计算毒代动力学参数。结果高、中、低三个剂量组的半衰期(t1/2)分别为(14.29±3.98)、(41.67±21.96)、(144.83±50.43)h,达峰时间(Tmax)分别为(0.10±0.06)、(0.08±0.00)、(0.08±0.00)h,峰浓度(Cmax)分别为(3.02±1.72)、(2.39±2.00)、(1.47±0.78)mg.L-1,曲线下面积AUC(0~24)分别为(8.47±3.08)、(9.36±2.31)、(7.49±0.46)mg.L-1.h。AUC及Cmax与剂量均不呈比例,且三种剂量的半衰期相差较远。结论马兜铃酸Ⅰ能迅速吸收入血,随后浓度逐渐降低,于24 h后仅存微量。在毒性剂量下,马兜铃酸Ⅰ在大鼠体内的毒代动力学过程出现了一定程度的变化,具有非线性动力学性质。
Objective To investigate the toxicokinetics of aristolochic acid I at three doses using repeated dose toxicity studies to understand the intrinsic link between systemic exposure and toxicity of aristolochic acid I under toxicological conditions. Provide reference materials for the study of safety evaluation and toxicity mechanism. Methods Rats were given intraperitoneal aristolochic acid I 30,15,5 mg.kg-1 once a day for 14 days. Plasma concentrations at different time points were determined. DAS pharmacokinetic procedures were used to determine the plasma concentration of The time data was fitted and the toxicokinetic parameters were calculated. Results The half-life (t1/2) of the high, middle and low dose groups were (14.29±3.98), (41.67±21.96), (144.83±50.43) h, and the peak time (Tmax) was (0.10±0.06). ), (0.08±0.00), (0.08±0.00) h, peak concentrations (Cmax) were (3.02±1.72), (2.39±2.00), (1.47±0.78) mg.L-1, and the area under the curve was AUC ( 0-24) were (8.47±3.08), (9.36±2.31), (7.49±0.46) mg.L-1.h, respectively. Both AUC and Cmax were not proportional to the dose, and the half-lives of the three doses were far apart. Conclusions Aristolochic acid I can be quickly absorbed into the blood, and then the concentration gradually decreases, leaving only trace amounts after 24 hours. At toxic doses, the toxicokinetic process of aristolochic acid I in rats has undergone a certain degree of change, with nonlinear dynamic properties.