New Insights into the Mechanism of Methoxyflurane Nephrotoxicity and Implications for Anesthetic Development (Part 1): Identification of the Nephrotoxic Metabolic Pathway

@article{Kharasch2006NewII,
  title={New Insights into the Mechanism of Methoxyflurane Nephrotoxicity and Implications for Anesthetic Development (Part 1): Identification of the Nephrotoxic Metabolic Pathway},
  author={Evan D. Kharasch and Jesara L Schroeder and H. Denny Liggitt and Sang Bong Park and Dale Whittington and Pamela Sheffels},
  journal={Anesthesiology},
  year={2006},
  volume={105},
  pages={726-736}
}
BACKGROUND Methoxyflurane nephrotoxicity results from biotransformation; inorganic fluoride is a toxic metabolite. [] Key Method Rats pretreated with phenobarbital, barium sulfate, or nothing were anesthetized with methoxyflurane, and renal function and urine methoxyflurane metabolite excretion were assessed. Phenobarbital effects on MDFA metabolism and toxicity in vivo were also assessed. Metabolism of methoxyflurane and MDFA in microsomes from livers of pretreated rats was determined in vitro.
New Insights into the Mechanism of Methoxyflurane Nephrotoxicity and Implications for Anesthetic Development (Part 2): Identification of Nephrotoxic Metabolites
TLDR
MethoxyFlurane nephrotoxicity seems to result from O-demethylation, which forms both fluoride and DCAA, which may explain why increased fluoride formation from methoxyflurane, but not other anesthetics, is associated with toxicity.
Analgesic use of inhaled methoxyflurane
  • A. Dayan
  • Medicine
    Human & experimental toxicology
  • 2016
TLDR
It is concluded from clinical experience in emergency medicine, surgical procedures and various experimental and laboratory investigations that the analgesic use of methoxyflurane in subanaesthetic doses in the Penthrox inhaler does not carry a risk of nephrotoxicity.
Human nephrotoxicity prediction models for three types of kidney injury based on data sets of pharmacological compounds and their metabolites.
The kidney is the most important organ for the excretion of pharmaceuticals and their metabolites. Among the complex structures of the kidney, the proximal tubule and renal interstitium are major
Adverse Drug Reactions With Halogenated Anesthetics
  • E. Kharasch
  • Medicine, Biology
    Clinical pharmacology and therapeutics
  • 2008
TLDR
This review focuses on adverse organ effects (hepatic, renal, and others) that are attributable to anesthetic metabolism and/or degradation that are associated with halogenated volatile anesthetics.
The use of methoxyflurane (Penthrox®) for procedural analgesia in the emergency department and pre-hospital environment
TLDR
Methoxyflurane is an efficacious analgesic agent in the emergency department and pre-hospital environment and performs favourably with a low chance of adverse events compared to other analgesic agents.
Halothane does not directly interact with genome DNA of A549 cells.
TLDR
It is found that irreversible impairment of the cell genome is initiated at a concentration as low as 1.5 mM, and it is suggested that the intracellular signalling pathway triggers the toxic effects of halothane.
Plasma fluoride concentrations during prolonged administration of isoflurane to a pediatric patient requiring renal replacement therapy
TLDR
This is a case report of prolonged isoflurane administration over 164 hours in a 2-year-old boy with acute sepsis-related renal failure and renal replacement therapy and the elimination of the inorganic fluoride.
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References

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New Insights into the Mechanism of Methoxyflurane Nephrotoxicity and Implications for Anesthetic Development (Part 2): Identification of Nephrotoxic Metabolites
TLDR
MethoxyFlurane nephrotoxicity seems to result from O-demethylation, which forms both fluoride and DCAA, which may explain why increased fluoride formation from methoxyflurane, but not other anesthetics, is associated with toxicity.
Human Kidney Methoxyflurane and Sevoflurane Metabolism: Intrarenal Fluoride Production as a Possible Mechanism of Methoxyflurane Nephrotoxicity
TLDR
The relative paucity of renal sevoflurane defluorination may explain the absence of clinical sev ofluran nephrotoxicity to date, despite plasma fluoride concentrations that may exceed 50 micro Meter.
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TLDR
Inorganic fluoride is responsible for the acute polyuric renal lesion which occurs after methoxyflurane administration, and Pretreatment with SKF 525-A decreased the metabolism of methoxyFLurane and ameliorated its nephrotoxicity.
The influence of age on the distribution, metabolism and excretion of methoxyflurane in Fischer 344 rats: a possible relationship to nephrotoxicity.
TLDR
It is likely that increased availability of methoxyflurane due to its greater storage in fat led to more inorganic fluoride production in older compared to younger rats, and the risk of nephrotoxicity is less in younger animals.
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TLDR
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TLDR
A high rate of methoxyflurane metabolism and increased susceptibility to the nephrotoxic effects of inorganic fluoride result in polyuric renal insufficiency in Fischer 344 rats.
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TLDR
Identification of P450 2E1 as the major anesthetic metabolizing enzyme in humans provides a mechanistic understanding of clinical fluorinated ether anesthetic metabolism and toxicity.
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TLDR
It is demonstrated that FDVE S-conjugates undergo P4503A-catalyzed sulfoxidation in rats in vivo, and this sulfoxidated pathway contributes to nephrotoxicity.
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TLDR
The use of methoxyflurane in clinical anesthesia should be restricted to situations where it offers specific advantages and where dosages less than 2.5 MAC hours can be attained.
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