New Insights into the Mechanism of Methoxyflurane Nephrotoxicity and Implications for Anesthetic Development (Part 2)

Abstract

Methoxyflurane nephrotoxicity seems to result from O-demethylation, which forms both fluoride and DCAA. Because their co-formation is unique to methoxyflurane compared with other volatile anesthetics and they are more toxic than fluoride alone, this suggests a new hypothesis of methoxyflurane nephrotoxicity. This may explain why increased fluoride formation from methoxyflurane, but not other anesthetics, is associated with toxicity. These results may have implications for the interpretation of clinical anesthetic defluorination, use of volatile anesthetics, and the laboratory methods used to evaluate potential anesthetic toxicity.

Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting

“…It undergoes dechlorination to 2, 2‐diflouro‐2‐methoxyacetic acid and O‐methylation to fluoride and dichloroacetic acid. It is likely that nephrotoxicity is because of a metabolic product apart from fluoride, such as dichloroacetic acid, as methoxyflurane causes more renal failure than other agents leading to a similar rise in free fluoride levels 34,36 . An alternative hypothesis is that intra‐renal metabolism of methoxyflurane generates intra‐renal fluoride to a greater extent than other fluorinated anaesthetics, such as sevoflurane, resulting in the increased renal toxicity of this agent 35 …”

Adverse Drug Reactions With Halogenated Anesthetics

“…Nephrotoxicity is absent in massive clinical fluoride intoxication. Although fluoride injection into animals caused renal toxicity, resultant plasma concentrations were extremely high (400 μmol/l), 19 while those producing concentrations approximating those after methoxyflurane anesthesia had no renal effects 20…”

“…Additionally, the theory that fluoride was the sole mechanism of methoxyflurane nephrotoxicity had become questionable. Owing to the need for a correct mechanistic understanding of anesthetic toxicity and the implications for anesthetics development, we reevaluated the mechanisms of methoxyflurane nephrotoxicity 19 , 21 , 22 . In animals, methoxydifluoroacetic acid, formed via methoxyflurane dechlorination, was neither nephrotoxic nor metabolized to fluoride.…”

“…Another potential explanation for methoxyflurane nephrotoxicity is that intrarenal, in addition to hepatic, formation of fluoride (and DCAA) may contribute to toxicity. Fluoride nephropathy appears dependent more on intrarenal than systemic concentrations 19 , 22 . Human kidney microsomes (which do not contain CYP2E1) substantially metabolized methoxyflurane (substrate for several CYPs) but not sevoflurane (metabolized exclusively by CYP2E1) 21 .…”

Methoxyflurane: a review with emphasis on its role in dental practice

“…51 More recently a new hypothesis of methoxyflurane nephrotoxicity proposed that it may result from O-demethylation which forms both fluoride and dichloroacetic acid. 52 The formation of the two compounds is unique to methoxyflurane compared to other volatile anaesthetics.…”