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

Abstract

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 (AUC0-∞) of theophylline was significantly smaller (2200 vs 1550 μg 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 AUC0–6 h of 1,3-dimethyluric acid was significantly greater (44.4 vs 456 μg min mL−1) compared with control rats. Moreover, the AUC0–6 h, 1,3-dimethyluric acid/ AUC0–∞, 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.