马兜铃酸I在大鼠体内的代谢特征研究

Studies on pharmacodynamic characteristics of aristolochic acid I in rats

目的 :研究口服马兜铃酸I(AA I)在大鼠体内的药物代谢动力学特点。方法 :以12 5I标记的AA I作为示踪剂 ,给予大鼠一次口服关木通水煎剂 10g·kg-1和12 5I标记AA I(含AA I37.2mg·L-1)的混合药液 ,测定全血12 5I AA I浓度及血浆蛋白结合率 ,采用 3P87程序拟合并计算药物代谢动力学参数。同时测定肝、肾等 9种脏器中的12 5I AA I含量 ,计算ID %、分布比值 ,观察上述指标随时间的动态变化 ,分析比较AA I在不同脏器的分布特点。结果 :大鼠一次口服关木通水煎剂后 ,AA I迅速吸收入血 ,于 30min达到高峰 ,持续至 1.5h ,随后其浓度逐渐降低 ,于 2 4h后仅存微量 ,给药后 10d时 6 8.9%的AA I以蛋白结合形式存在。经拟合其特征符合血管外给药二室模型 ,所得参数显示 :口服AA I在 0 .74h达峰 (Tmax) ,达峰浓度 (Cmax) 0 .92mg·L-1,分布半衰期 (t1/ 2α) 0 .6 8h ,消除半衰期 (t1/ 2 β) 2 0 .4 6h ,表观分布容积 (V/F) 87.39mL ,总清除率CL(s) 5 .85mL·h-1(0 .10mL·min-1)。服药后AA I迅速分布至全身 ,5min时即已达到分布比值的高峰 ,2 4～ 4 8h处于最低水平 ;而后AA I在肝、肾的分布比值又不断增高 ,肝脏在第 4d达峰 ,而后再次下降 ;在肾脏则继续升高 ,至观察结束 (第 4 0d)最为突出 ,明显高于其他脏器 (P <0 .

Objective: To study pharmacodynamic characteristics by oral administration aristolochic acid I (AA-I) in rats. Method: After one-time oral administration of Aristolochiae manshuriensis decoction 10 g·kg -1 and 125 I labeled AA-I(containing AA-I 37.2 μg·mL -1), whole blood concentration of 125 I-AA-I and the binding rate of serum albumin were detected in 69 normal wistar male rats. Metabolic dynamic parameters were calculated by program 3P87 with a two compartment model. The distribution ratio and ID% of nine viscera or tissue were measured and compared with other until the 40th day. Result: After oral administration, AA-I was rapidly absorbed into the blood and reached its peak at 30 minutes and lasted till 90 minutes. AA-I concentration in the blood gradually declined afterwards. 24 hours later, only few AA-I could be detected. By the 10th day, 68.5% of AA-I presented as the binding type with serum albumin. Pharmacodynamic parameters were calculated as follows: Tmax 0.74 h, C max 0.92 μg·mL -1, t 1/2α 0.68 h, t 1/2β 20.46 h, V/F 87.39 mL, CL(s) 5.85 mL·h -1 (0.10 mL·min -1). On the other hand, after oral administration AA-I was rapidly distributed to all the viscera or tissue, whose peak appeared in 5 minutes and the vallecula was from 24 to 48 hours. The distribution ratio of AA-I rose in the kidney after 24 hours, and it showed the highest level in the kidney and in the liver by the 4th day compared with other organs or tissue (P<0.05). However, the distribution ratio of AA-I in the kidney became the most dominant one after the 30th and the 40th day compared with the others(P<0.05). Conclusion: AA-I is rapidly absorbed after oral administration in rats. Its distribution has the organ specificity, which is characterized as the possible partial metabolism in the liver and the accumulation in the kidney because of rather slower elimination. The characteristics may be related to the long term nephrotoxicity of AA-I.