Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism.

It has been reported that the non-renal clearance of furosemide was significantly faster in rats pretreated with phenobarbital but was not altered in rats pretreated with 3-methylcholanthrene. However, no studies on other cytochrome P450 (CYP) isozymes have yet been reported in rats. Furosemide 20 mg/kg was administered intravenously to rats pretreated with various CYP inducers--3-methylcholanthrene, orphenadrine citrate and isoniazid, inducers of CYP1A1/2, 2B1/2 and 2E1, respectively, in rats--and inhibitors--SKF-525A (a non-specific inhibitor of CYP isozymes), sulfaphenazole, cimetidine, quinine hydrochloride and troleandomycin, inhibitors of CYP2C6, 2C11, 2D and 3A1/2, respectively, in rats. The non-renal clearance of furosemide was significantly faster (55.9% increase) in rats pretreated with isoniazid, but slower in those pretreated with cimetidine or troleandomycin (38.5% and 22.7% decreases, respectively), than controls. After incubation of furosemide with baculovirus-infected insect cells expressing CYP2C11, 2E1, 3A1 or 3A2, furosemide was metabolized via CYP2C11, 2E1, 3A1 and 3A2. These findings could help explain possible pharmacokinetic changes of furosemide in various rat disease models (where CYP2C11, 2E1, 3A1 and/or CYP3A2 are altered) and drug-drug interactions between furosemide and other drugs (mainly metabolized via CYP2C11, 2E1, 3A1 and/or 3A2).