Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous torasemide in rats

In order to find whether torasemide is metabolized via CYP isozymes in rats, torasemide at a dose of 2 mg/kg was infused in rats pretreated with SKF 525-A, a non-specific CYP isozyme inhibitor in male Sprague-Dawley rats. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) of torasemide was significantly greater in rats pretreated with SKF 525-A (a non-specific CYP isozyme inhibitor in rats) than that in control rats (3570 versus 1350 μg min/ml). This indicated that torasemide is metabolized via CYP isozymes in rats. Hence, torasemide was infused in rats pretreated with various enzyme inducers and inhibitors to find what types of CYP isozymes are involved in the metabolism of torasemide in rats. The AUC values were not significantly different in rats pretreated with 3-methylcholanthrene, phenobarbital, isoniazid, quinine and troleandomycin (main inducers of CYP1A1/2, CYP2B1/2, and CYP2E1, and main inhibitors of CYP2D1 and CYP3A1/2 in rats, respectively) compared with those in respective control rats. However, in rats pretreated with dexamethasone (a main inducer of CYP3A1/2 in rats), the AUC was significantly smaller than that in control rats (1290 versus 1590 μg min/ml). Dexamethasone probably also induces rat CYP2C11; this could be due to an increase in CYP2C11 in rats pretreated with dexamethasone. It has been reported from our laboratories that in rats pretreated with sulfaphenazole (a main inhibitor of CYP2C11 in rats) the AUC was significantly greater than that in control rats (2970 versus 1610 μg min/ml). The above data suggested that torasemide could be metabolized in male rats mainly via CYP2C11.