Chemical and enzymatic oxidation of furosemide: formation of pyridinium salts.
Furosemide (Lasix) is frequently used in the treatment of cardiovascular and renal disease. Only one metabolite, furosemide glucuronide, has ever been identified. Oxidation of furosemide by cytochrome P450 has been demonstrated, but the metabolite(s) has never been identified. The oxidation of furosemide by dimethyldioxirane in acetone and by liver microsomal incubations was explored in this study. The first observable product from dimethyldioxirane oxidation was a ring-expanded enone resulting from an intramolecular condensation of the aldehyde group of the enonal, the secondary amine, and the carboxylic acid in a Mannich-like reaction. Keto-enol tautomerization and opening of the lactone gave a stable pyridinium salt. The pyridinium salt was also observed in the microsomal incubations of furosemide. The presence of an internal nucleophile in furosemide may have a significant effect on the toxicology and possibly the pharmacology of this furan.
Chen
Ling-Jen
LJ
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. ljferguson@lrri.org
Burka
Leo T
LT
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004232:Diuretics / Q000737:chemistry / Q000378:metabolism; D004852:Epoxy Compounds / Q000737:chemistry; D005665:Furosemide / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012492:Salts; D021241:Spectrometry, Mass, Electrospray Ionization
D004232:Diuretics; D004852:Epoxy Compounds; D011726:Pyridinium Compounds; D012492:Salts; D005665:Furosemide; D003577:Cytochrome P-450 Enzyme System; C064455:dimethyldioxirane