Pharmacokinetics and nephrotoxicity of aristolochic acid in rabbits

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 2.0 mg/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 2.0 mg/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.