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.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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).
Yang
Kyung H
KH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Choi
Young H
YH
Lee
Unji
U
Lee
Joo H
JH
Lee
Myung G
MG
D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002927:Cimetidine / Q000008:administration & dosage / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004232:Diuretics / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D004347:Drug Interactions; D020536:Enzyme Activators / Q000008:administration & dosage / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005665:Furosemide / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D006207:Half-Life; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007538:Isoniazid / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008748:Methylcholanthrene / Q000008:administration & dosage / Q000494:pharmacology; D009966:Orphenadrine / Q000008:administration & dosage / Q000494:pharmacology; D011335:Proadifen / Q000008:administration & dosage / Q000493:pharmacokinetics; D011803:Quinine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014217:Troleandomycin / Q000008:administration & dosage / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects
D004232:Diuretics; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D008748:Methylcholanthrene; D005665:Furosemide; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D011803:Quinine; D009966:Orphenadrine; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; D007538:Isoniazid