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.