title: 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 (1,040 versus 1,750 microg 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 x 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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Ok Kyung
authors.initials: OK
authors.lastname: Suh
authors.forename: Myung Gull
authors.initials: MG
authors.lastname: Lee
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001796:Blood Protein Disorders / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D004790:Enzyme Induction; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000172:deficiency*; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D012709:Serum Albumin; D014527:Uric Acid; D013806:Theophylline; C031274:1,3-dimethyluric acid; D019388:Cytochrome P-450 CYP1A2