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.

In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. II. A reevaluation of hepatic metabolic pathways.

Methoxyflurane (2,2-dichloro-1,1-difluoro-ethyl methyl ether) is believed to be metabolized via two convergent metabolic pathways. The relative flux through these two metabolic pathways has been investigated using a combination of in vivo surface coil NMR techniques and in vitro analyses of urinary metabolites. Analysis of the measured concentrations of inorganic fluoride, oxalate, and methoxydifluoroacetate in the urine of methoxyflurane-treated rats for 4 days after anesthesia indicates that the anesthetic is metabolized primarily via dechlorination to yield methoxydifluoroacetate. The methoxydifluoroacetate is largely excreted without further metabolism, although a small percentage of this metabolite is broken down to yield fluoride and oxalate, as determined by urine analysis of rats dosed with synthetic methoxydifluoroacetate. At early times after methoxyflurane exposure, the relative concentrations of methoxyflurane metabolites indicate that a significant fraction of the metabolic flux occurs via a different pathway, presumably demethylation, to yield dichloroacetate as an intermediate. Direct analysis of dichloroacetate in the urine using water-suppressed proton NMR indicates that the level of this metabolite is below the detection threshold of the method. Measurements made on the urine of rats dosed directly with dichloroacetate indicate that this compound is quickly metabolized, and dichloroacetate levels in urine are again found to be below the detection threshold. These results demonstrate the quantitative importance of the dechlorination pathway in the metabolism of methoxyflurane in rats.