title: New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites.
abstract: BACKGROUND
  Methoxyflurane nephrotoxicity results from its metabolism, which occurs by both dechlorination (to methoxydifluoroacetic acid [MDFA]) and O-demethylation (to fluoride and dichloroacetic acid [DCAA]). Inorganic fluoride can be toxic, but it remains unknown why other anesthetics, commensurately increasing systemic fluoride concentrations, are not toxic. Fluoride is one of many methoxyflurane metabolites and may itself cause toxicity and/or reflect formation of other toxic metabolite(s). This investigation evaluated the disposition and renal effects of known methoxyflurane metabolites.
  
  
  METHODS
  Rats were given by intraperitoneal injection the methoxyflurane metabolites MDFA, DCAA, or sodium fluoride (0.22, 0.45, 0.9, or 1.8 mmol/kg followed by 0.11, 0.22, 0.45, or 0.9 mmol/kg on the next 3 days) at doses relevant to metabolite exposure after methoxyflurane anesthesia, or DCAA and fluoride in combination. Renal histology and function (blood urea nitrogen, urine volume, urine osmolality) and metabolite excretion in urine were assessed.
  
  
  RESULTS
  Methoxyflurane metabolite excretion in urine after injection approximated that after methoxyflurane anesthesia, confirming the appropriateness of metabolite doses. Neither MDFA nor DCAA alone had any effects on renal function parameters or necrosis. Fluoride at low doses (0.22, then 0.11 mmol/kg) decreased osmolality, whereas higher doses (0.45, then 0.22 mmol/kg) also caused diuresis but not significant necrosis. Fluoride and DCAA together caused significantly greater tubular cell necrosis than fluoride alone.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, 660 South Euclid Avenue, St. Louis, MO 63110-1093, USA. kharasch@wustl.edu
authors.forename: Evan D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: Jesara L
authors.initials: JL
authors.lastname: Schroeder
authors.forename: H Denny
authors.initials: HD
authors.lastname: Liggitt
authors.forename: Dustin
authors.initials: D
authors.lastname: Ensign
authors.forename: Dale
authors.initials: D
authors.lastname: Whittington
mesh_terms: D000776:Anesthesiology / Q000639:trends*; D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D003999:Dichloroacetic Acid / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008733:Methoxyflurane / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012969:Sodium Fluoride / Q000378:metabolism / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018685:Anesthetics, Inhalation; D008733:Methoxyflurane; D012969:Sodium Fluoride; D003999:Dichloroacetic Acid