IN VIVO F-19 NMR STUDIES OF THE METABOLISM OF FLUROINATED ANESTHETICS

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Several lines of evidence indicate that some post-surgical illnesses are caused by toxic metabolites of the anesthetics used during surgery. The presence of fluorine atoms in most of the general anesthetics in clinical use makes F-19 nuclear magnetic resonance (NMR) an ideal technique for analyzing the metabolism of these compounds, both in vitro and in vivo. Using this technique, studies of the metabolism of halothane, methoxyflurane, and enflurane have been carried out. In vivo studies of hepatic metabolism in anesthetized rats utilized a surface coil tuned to the fluorine resonance and positioned directly above the liver of animals in which the intervening layer of muscle had been previously removed surgically. Methoxyflurane, perhaps the most toxic of the fluorinated anesthetics used and one now confined to veterinary use, has been postulated to undergo both oxidative, P450 dependent metabolism to methoxydifluoroacetic acid, and demethylation to yield dichloracetic acid plus inorganic fluoride. In vivo NMR studies have indicated significant levels of an organic fluorinated metabolite in addition to the methoxyflurane. This metabolite was identified as methoxydifluoroacetic acid by comparison of the NMR parameters with the directly synthesized metabolite. However, no resonance corresponding to inorganic fluoride is observed in vivo, due either to excessive broadening and/or rapid excretion. Since the metabolism of several anesthetics, particularly halothane, is postulated to involve free radical intermediates, strategies for observeration of such species by NMR are being evaluated. In particular, NMR active, fluorinated spin traps, analogous to those utilized to study free radical metabolism by ESR, are under development. The reducing environments of most in vivo systems will be sufficient to yield diamagnetic spin adducts, which can be monitoried by NMR.