硝酸铀酰诱导的急性肾衰竭对大鼠静脉注射茶碱药代动力学的影响：CYP2E1诱导在1,3-二甲基尿酸形成中的作用

Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of intravenous theophylline in rats: the role of CYP2E1 induction in 1,3-dimethyluric acid formation.

作者信息

Yu Su Yeon, Chung Hye Chin, Kim Eun Jung, Kim So Hee, Lee Inchull, Kim Sang Geon, Lee Myung Gull

机构信息

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Korea.

出版信息

J Pharm Pharmacol. 2002 Dec;54(12):1687-92. doi: 10.1211/002235702333.

DOI:10.1211/002235702333

PMID:12542900

Abstract

In rats with acute renal failure induced by uranyl nitrate, the hepatic microsomal cytochrome P450 (CYP) 2E1 and CYP3A23 increased 2-4- and 4-times, respectively, CYP2C11 decreased to 80% of control, but the levels of CYP1A2 and CYP2B1/2 were not changed. It has been reported that theophylline was metabolized to 1,3-dimethyluric acid by CYP1A2 and CYP2E1 and 1-methylxanthine via CYP1A2, which was metabolized further to 1-methyluric acid via xanthine oxidase in rats. Hence, it was expected that the formation of 1,3-dimethyluric acid would show an increase in rats with renal failure as a result of induction of CYP2E1. The pharmacokinetics of theophylline were compared in control rats and rats with renal failure after intravenous administration of aminophylline, 5 mg kg(-1) as theophylline. In rats with renal failure, the plasma concentrations of theophylline were considerably lower and the resultant total area under the plasma concentration-time curve from time zero to time infinity (AUC(0- infinity )) of theophylline was significantly smaller (2,200 vs 1,550 microg min mL(-1)) compared with control rats. In rats with renal failure, the plasma concentrations of 1,3-dimethyluric acid were considerably higher and the resultant AUC(0-6 h) of 1,3-dimethyluric acid was significantly greater (44.4 vs 456 microg min mL(-1)) compared with control rats. Moreover, the AUC(0-6 h, 1,3-dimethyluric acid)/AUC(0- infinity, theophylline) ratio increased from 2.02% in control rats to 29.4% in rats with renal failure. The in-vitro intrinsic 1,3-dimethyluric acid formation clearance was significantly faster in rats with renal failure (734 vs 529 10(-6) mL min(-1)) compared with control rats using hepatic microsomal fraction. The results led us to conclude that in rats with uranyl nitrate-induced renal failure after the administration of aminophylline, 5 mg kg(-1) as theophylline, there was an increase in the formation of 1,3-dimethyluric acid as a result of an increase in CYP2E1 expression.

摘要

在由硝酸铀酰诱导的急性肾衰竭大鼠中，肝微粒体细胞色素P450（CYP）2E1和CYP3A23分别增加了2至4倍和4倍，CYP2C11降至对照的80%，但CYP1A2和CYP2B1/2的水平未改变。据报道，在大鼠中，茶碱经CYP1A2和CYP2E1代谢为1,3 - 二甲基尿酸，并经CYP1A2代谢为1 - 甲基黄嘌呤，后者再经黄嘌呤氧化酶进一步代谢为1 - 甲基尿酸。因此，预计由于CYP2E1的诱导，肾衰竭大鼠中1,3 - 二甲基尿酸的形成会增加。静脉注射氨茶碱（以茶碱计5 mg kg⁻¹）后，比较了对照大鼠和肾衰竭大鼠中茶碱的药代动力学。在肾衰竭大鼠中，茶碱的血浆浓度显著较低，茶碱从时间零至时间无穷大的血浆浓度 - 时间曲线下总面积（AUC(0 - ∞)）与对照大鼠相比明显更小（2200对1550 μg min mL⁻¹）。在肾衰竭大鼠中，1,3 - 二甲基尿酸的血浆浓度显著更高，1,3 - 二甲基尿酸的AUC(0 - 6 h)与对照大鼠相比明显更大（44.4对456 μg min mL⁻¹）。此外，AUC(0 - 6 h, 1,3 - 二甲基尿酸)/AUC(0 - ∞, 茶碱)比值从对照大鼠的2.02%增加到肾衰竭大鼠的29.4%。使用肝微粒体部分，与对照大鼠相比，肾衰竭大鼠体外1,3 - 二甲基尿酸形成清除率明显更快（734对529×10⁻⁶ mL min⁻¹）。结果使我们得出结论，在以茶碱计5 mg kg⁻¹给予氨茶碱后，硝酸铀酰诱导的肾衰竭大鼠中，由于CYP2E1表达增加，1,3 - 二甲基尿酸的形成增加。