Effects of CYP inducers and inhibitors on the pharmacokinetics of intravenous theophylline in rats: involvement of CYP1A1/2 in the formation of 1,3-DMU.
The types of hepatic cytochrome P450 (CYP) isozymes responsible for the metabolism of theophylline and for the formation of 1,3-dimethyluric acid (1,3-DMU) in rats in-vivo does not seem to have been studied at the dose ranges of dose-independent metabolic disposition of theophylline in rats (up to 10 mg kg(-1)). Therefore, theophylline (5 mg kg(-1)) was administered i.v. to male Sprague-Dawley rats pretreated with various inducers and inhibitors of CYP isozymes. In rats pretreated with 3-methylcholanthrene (3-MC), orphenadrine or dexamethasone (main inducers of CYP1A1/2, CYP2B1/2 and CYP3A1/2, respectively, in rats), the time-averaged non-renal clearance (CLNR) of theophylline was significantly faster than in their respective controls (1260, 42.7 and 69.0% increases, respectively). However, in rats pretreated with troleandomycin (a major inhibitor of CYP3A1/2 in rats), CLNR was significantly slower than in the controls (50.7% decrease). The 24 h urinary excretion of 1,3-DMU was increased significantly only in rats pretreated with 3-MC. The ratio of area under the curve for 1,3-DMU and theophylline (AUC1,3-DMU/AUCtheophylline) was increased significantly in rats pretreated with 3-MC (160% increase) and decreased significantly in rats pretreated with troleandomycin (50.1% decrease); however, the ratio was not increased in rats pretreated with dexamethasone. These data suggest that theophylline is primarily metabolized via CYP1A1/2, CYP2B1/2, and CYP3A1/2, and that 1,3-DMU is primarily formed via CYP1A1/2, and possibly CYP3A1/2, in rats.
Yang
Kyung H
KH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Lee
Joo H
JH
Lee
Myung G
MG
D000818:Animals; D019540:Area Under Curve; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology*; D006207:Half-Life; D007262:Infusions, Intravenous; D007538:Isoniazid / Q000494:pharmacology; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008748:Methylcholanthrene; D009966:Orphenadrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D001551:Benz(a)Anthracenes; D020536:Enzyme Activators; D010726:Phosphodiesterase Inhibitors; D014527:Uric Acid; D008748:Methylcholanthrene; D003907:Dexamethasone; D009966:Orphenadrine; D013806:Theophylline; C031274:1,3-dimethyluric acid; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D007538:Isoniazid