Quantitative Assessment of Protective Effects of Antioxidant Agents against Drug-Induced Nephrotoxicity Using Dynamic Contrast-Enhanced Computed Tomography

摘要

Purpose: The purpose of this study was to develop a method for quantifying the extent of renal dysfunction due to drug-induced nephrotoxicity using dynamic contrast-enhanced computed tomography (DCE-CT) and to investigate the protective effects of various antioxidant agents against cis-dichlorodiammineplatinum (cisplatin)-induced nephrotoxicity in rats using this method. Materials and Methods: The DCE-CT studies were performed in 8-week-old male Sprague-Dawley rats. The CT scanning started 4 s before a bolus intravenous injection of iodinated contrast agent (CA) (150 mgI/kg) from the tail vein using an automatic injector and lasted 90 s at 1-s intervals. The contrast clearance per unit renal volume (K1) was estimated from the DCE-CT data using the Patlak model. The renal volume (V) was calculated by manually delineating the kidney on the CT image. The contrast clearance of the entire kid-ney (K) was obtained by . First, to investigate the effect of CA itself, the DCE-CT studies were performed without injecting cisplatin 2, 4, and 7 days after the first DCE-CT study on day 0. Second, to investigate the effect of injected dose of cisplatin, the DCE-CT study was performed after the intraperitoneal (i.p.) injection of cisplatin (1.8 mg/kg) and was repeated every other day for one week. Finally, to investigate the protective effects of antioxidant agents [L-arginine (300 mg/kg), N-acetylcysteine (500 or 1000 mg/kg), methimazole (40 mg/kg), captopril (60 mg/kg), and taurine (750 mg/kg)], the DCE-CT studies were performed on days 0, 2, 4, and 7 after the i.p. injection of cisplatin (3.6 mg/kg). For comparison, the DCE-CT data were also acquired without injecting the antioxidant agents (CDDP group). Results: When cisplatin was not injected, there were no significant changes in the K value as compared to that on day 0 within the studied period. The K valuesignificantly (p < 0.05) decreased with increasing dose of cisplatin. Although some differences were observed in the extent of change in the K value normalized by that on day 0, depending on the antioxidant agents and their injected dose and schedule, the normalized K values on day 7 in the groups injected with the antioxidant agents were significantly higher than those in the CDDP group, suggesting that the antioxidant agents studied here had protective effects against cisplatin-induced nephrotoxicity in varying degrees. Conclusion: Our method appears useful for quantitatively evaluating the protective effects of antioxidant agents against cisplatin-induced nephrotoxicity and for investigating the optimal injected dose and schedule of the agents, because it allows repeated measurements of split renal function in a single animal.