New Insights into the Mechanism of Methoxyflurane Nephrotoxicity and Implications for Anesthetic Development (Part 1)

Abstract

Fluoride from methoxyflurane anesthesia derives from O-demethylation. Phenobarbital increases in methoxyflurane toxicity do not seem attributable to methoxyflurane dechlorination, MDFA toxicity, or MDFA metabolism to another toxic metabolite, suggesting that nephrotoxicity is attributable to methoxyflurane O-demethylation. Fluoride, one of many metabolites from O-demethylation, may be toxic and/or reflect formation of a different toxic metabolite. These results may have implications for interpreting anesthetic defluorination, volatile anesthetic use, and methods to evaluate anesthetic toxicity.

Efficacy and safety of inhaled low-dose methoxyflurane for acute paediatric pain: A systematic review

“…17 Release of fluoride ions has been linked with renal tubular damage when methoxyflurane is inhaled for >5 h at minimum alveolar concentration (MAC), resulting in serum fluoride concentrations exceeding 90 mmol/L, although fluoride toxicity alone is considered not the be a single cause. 32,33 The absence of renal toxicity with analgesic use of methoxyflurane is likely to reflect the low dose and short duration of inhalation: following a 3 mL dose of inhaled methoxyflurane serum levels of fluoride do not exceed 10 mmol/ L. 23 This level of exposure is well under the threshold fluoride concentration of 40 mmol/L (following inhalation of methoxyflurane at MAC for 2.0 h) below which no biochemical evidence of renal damage has been observed. 32 Based on these findings, the safety margin of inhaled methoxyflurane has been calculated to be 2.7-fold to 8.0-fold.…”

Analgesic use of inhaled methoxyflurane

“…Methoxyflurane is rapidly metabolized in humans by oxidative demethylation and defluorination (Figure 3). 16,[19][20][21][22][23] In humans, including patients given methoxyflurane as an anaesthetic or as an analgesic, healthy women in labour and healthy volunteers, the pharmacokinetics and metabolism of methoxyflurane have been studied mainly by following blood and urinary concentrations of the parent compound, its principal metabolites (fluoride and dichloroacetic acid (DCAA)) and their relationship to the inhaled concentration, as well as the total inhaled dose of methoxyflurane given either in higher doses to produce anaesthesia or in smaller doses to produce analgesia. 16,19,[21][22][23][24][25][26][27] Absorption is rapid, hence the fast onset of the analgesic action, due to the physicochemical characteristics of methoxyflurane, and blood levels plateau after less than 1 h of constant exposure.…”

“…No report has been found that the proposed limit of serum fluoride 40 mmol/L has not been 'safe' under normal circumstances, that is, exposures up to 2.0 MAC-hours have not been associated with nephrotoxicity. 22,23 Results from the recent clinical trial of Spruyt et al in bone marrow biopsy patients 49 have demonstrated the overall safety in use of short-term methoxyflurane analgesia and have shown that although its use was associated with a rise in total fluoride in serum, the level did not reach even the 'safe upper limit' proposed by Cousins and Mazze 16 (see Figure 4 and Table 4). It is noteworthy that no cases of methoxyflurane-induced nephrotoxicity have been reported in children after full anaesthesia with this agent.…”

Methoxyfluran beim traumaassoziierten Schmerz – Fallberichte und Literaturüberblick

“…Der nephrotoxische Effekt wurde bisher nur bei hohen anästhetischen Dosen beobachtet. Man nimmt an, dass die durch den Abbauprozess entstandenen anorganischen Fluoridionen, insbesondere in Kombination mit Dichloressigsäure, hauptverantwortlich für die Nierenschädigungen sind [20,26,32,33]. Nach Cousins und Mazze ist bei einem Serumfluoridspiegel < 40 µmol/l und bei der Inhalation von Methoxyfluran von ≤ 2,0 MAC-Stunden nicht mit Nierenschädigungen zu rechnen [34].…”