In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. I. Verification and quantitation of methoxydifluoroacetate.
The elimination and metabolism of the fluorinated inhalation anesthetic methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether) in rats has been monitored using in vivo 19F nuclear magnetic resonance at 8.45 T. The elimination of methoxyflurane from rat liver as measured using a surface coil is a first order process when measured beginning 2-3 hr after the end of methoxyflurane anesthesia over a period of 12 hr. The rate constant for hepatic methoxyflurane elimination is dependent upon the duration of anesthesia, varying from 0.24 hr-1 for 15 min of anesthesia to 0.07 hr-1 for 1 hr of anesthesia. Methoxyflurane was shown to be metabolized in the liver to methoxydifluoroacetate using the surface coil method. No resonance for hepatic fluoride ion could be observed in vivo. Pure sodium methoxydifluoroacetate was synthesized in order to confirm the identity of the resonances in liver and urine. 19F NMR spectra of urine collected from anesthetized rats contain resonances for two methoxyflurane metabolites, methoxydifluoroacetate and inorganic fluoride. Studies with liver homogenates imply that fluoride is quickly cleared from the liver and eliminated from the body through the urine, explaining the inability to observe hepatic fluoride using a surface coil. The 19F NMR resonance for inorganic fluoride in urine was found to be broadened by interaction with metal ions, since the broadening could be eliminated by treatment with chelating resin.
Selinsky
B S
BS
National Institute of Environmental Health Sciences, Laboratory of Molecular Biophysics, Research Triangle Park, North Carolina 27709.
Perlman
M E
ME
London
R E
RE
D000085:Acetates / Q000032:analysis / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008733:Methoxyflurane / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats
D000085:Acetates; C055934:difluoromethoxyacetic acid; D008733:Methoxyflurane