Pharmacokinetics of intravenous theophylline in mutant Nagase analbuminemic rats

Abstract

It was obtained from our laboratories that the expression of hepatic microsomal cytochrome P450 (CYP) 1A2 increased approximately 3.5 times in mutant Nagase analbuminemic rats (NARs, an animal model for human familial analbuminemia), and theophylline was reported to be metabolized to 1,3-dimethyluric acid (1,3-DMU) and 1-methylxanthine (which was further metabolized to 1-methyluric acid, 1-MU, via xanthine oxidase) via CYP1A2 in rats. Hence, the pharmacokinetic parameters of theophylline, 1,3-DMU and 1-MU were compared after intravenous administration of aminophylline, 5 mg/kg as theophylline, to control Sprague-Dawley rats and NARs. In NARs, the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of theophylline was significantly smaller (1040 versus 1750 μg min/ml) than that in control rats and this could be due to significantly faster renal clearance (CL R, 1.39 versus 0.571 ml/min/kg, due to inhibition of renal reabsorption of unchanged theophylline) and nonrenal clearance (CL NR, 3.36 versus 2.25 ml/min/kg, due to 3.5-fold increase in CYP1A2) than those in control rats. Based on in vitro hepatic microsomal studies, the intrinsic 1,3-DMU formation clearance was significantly faster in NARs than that in control rats (267 versus 180 × 10 −6 ml/min). After intravenous administration of 1,3-DMU, the renal secretion of 1,3-DMU was inhibited in NARs. Inhibition of renal secretion or reabsorption of various compounds in NARs was also discussed.