马兜铃酸Ⅰ在大鼠体内的毒代动力学

Toxicokinetics of aristolochic acid Ⅰ in rat

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I 30、15、5mg·kg^-1，每天1次，连续14d，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24h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。

Aim To study toxicokinetics of aristolochic acid I at the three doses adopted in toxicology research,and explore the relation- ship between exposure level and toxicity in order to provide information to safety evaluation and toxicity mechanism, Methods Plasma concentration at different time was determined after continuous oral administration at the dose of 30,15 and 5 mg·kg^ -1 once daily for 14 days. Data of concentration-time were fitted and toxicokinetics parameters were calculated by DAS software then. Results The parameters of high,middle and low dose were as follows： t1/2 were （14.29±3.98）,（41.67±21.96） and （144.83±50.43 ） h, Tmax, were （0.10±0.06）,（0.08±0.00） and （0.08±0.00）h,Cmax were （3.02±1.72）,（2.39±2.00） and （1.47±0.78） mg·L^-1, AUC（0-24） were （8.47±3.08）,（9.36±2.31） and （7.49±0.46） mg·L^-1·h, respectively. AUC and Cmax were both not proportional to dose,and the half life was very different among the three doses, Conclusion The absorption of aristolochic acid I was quick after continuous oral administration, and then the plasma concentration decreased gradually and microamount was detected 24 h later. Toxicoki- netics of aristolochic acid I was altered at toxic dose, It indicated that the nonlinear toxicokinetics characteristic of aristolochic acid I took place in the studied dose range.