Chen Shih-Ming, Fan Mei-Yu, Tseng Chia-Chi, Ho Yih, Hsu Kuang-Yang
School of Pharmacy, Department of Pharmaceutical Sciences, Taipei Medical University, 250 Wu-Hsing St., Taipei 110-31, Taiwan.
Toxicon. 2007 Aug;50(2):180-8. doi: 10.1016/j.toxicon.2007.03.011. Epub 2007 Apr 1.
Aristolochic acids (AAs) which exist in plants of the genus Aristolochia are the toxins responsible for aristolochic acid nephropathy (AAN). To investigate the pharmacokinetics and nephrotoxicity of AAs, rabbits were used in this study. The plasma concentrations of the main components of AAs, aristolochic acid I (AA I) and aristolochic acid II (AA II), were determined by a validated high-performance liquid chromatographic method. After intravenous administration of different doses (0.25, 0.5, 1.0, and 2.0mg/kg) of aristolochic acid sodium (AANa) to 4 respective groups of rabbits (n=6 for each dose), linear relationships between the doses of AA I and AA II and the area under the plasma concentration curve (AUC) were found to exist (p<0.001). AANa was also given in escalating doses (0.5, 1.0, and 2.0mg/kg) to the same rabbits at 7-day intervals. The clearance rates of both AA I and AA II significantly decreased with the escalating dose (p<0.001). A nonlinear relationship between the dose and AUC was obtained. Kidney specimens of rabbits were obtained to observe morphological changes on days 1 and 7 after AANa administration. The renal lesions caused by AAs consisted of progressive and dose-dependent tubular damage. However, no remarkable changes in the morphology of glomeruli were observed.
马兜铃酸（AAs）存在于马兜铃属植物中，是导致马兜铃酸肾病（AAN）的毒素。为了研究马兜铃酸的药代动力学和肾毒性，本研究使用了兔子。采用经过验证的高效液相色谱法测定马兜铃酸主要成分马兜铃酸I（AA I）和马兜铃酸II（AA II）的血浆浓度。将不同剂量（0.25、0.5、1.0和2.0mg/kg）的马兜铃酸钠（AANa）分别静脉注射给4组兔子（每组剂量n = 6）后，发现AA I和AA II的剂量与血浆浓度曲线下面积（AUC）之间存在线性关系（p<0.001）。还以递增剂量（0.5、1.0和2.0mg/kg）每隔7天给同一只兔子注射AANa。随着剂量递增，AA I和AA II的清除率均显著降低（p<0.001）。得到了剂量与AUC之间的非线性关系。在注射AANa后第1天和第7天获取兔子的肾脏标本，观察形态学变化。马兜铃酸引起的肾脏病变包括进行性和剂量依赖性的肾小管损伤。然而，未观察到肾小球形态有明显变化。
