title: Compound A uptake and metabolism to mercapturic acids and 3,3,3-trifluoro-2-fluoromethoxypropanoic acid during low-flow sevoflurane anesthesia: biomarkers for exposure, risk assessment, and interspecies comparison.
abstract: BACKGROUND
  Sevoflurane is degraded during low-flow anesthesia to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether ("compound A"), which causes renal necrosis in rats but is not known to cause nephrotoxicity in surgical patients. Compound A is metabolized to glutathione S-conjugates and then to cysteine S-conjugates, which are N-acetylated to mercapturic acids (detoxication pathway), or metabolized by renal beta-lyase to reactive intermediates (toxification pathway) and excreted as 3,3,3-trifluoro-2-fluoromethoxypropanoic acid. This investigation quantified compound A metabolites in urine after low-flow sevoflurane administration, to assess relative flux via these two pathways.
  
  
  METHODS
  Patients (n = 21) with normal renal function underwent low-flow (11 min) sevoflurane anesthesia designed to maximize compound A formation. Inspiratory, expiratory, and alveolar compound A concentrations were quantified. Urine mercapturic acids and 3,3,3-trifluoro-2-fluoromethoxypropanoic acid concentrations were measured by gas chromatography and mass spectrometry.
  
  
  RESULTS
  Sevoflurane exposure was 3.7 +/- 2.0 MAC-h. Inspired compound A maximum was 29 +/- 14 ppm; area under the inspired concentration versus time curve (AUCinsp) was 78 +/- 58 ppm x h. Compound A dose, calculated from pulmonary uptake, was 0.39 +/- 0.35 mmol (4.8 +/- 4.0 micromol/kg) and correlated with AUCinsp (r2 = 0.84, P < 0.001). Mercapturic acids excretion was complete after 2 days, whereas 3,3,3-trifluoro-2-fluoromethoxypropanoic acid excretion continued for 3 days in some patients. Total (3-day) mercapturates and fluoromethoxypropanoic acid excretion was 95 +/- 49 and 294 +/- 416 micromol, respectively (1.2 +/- 0.6 and 3.6 +/- 5.0 micromol/kg).
  
  
  CONCLUSIONS
  Compound A doses during 3.7 MAC-h, low-flow sevoflurane administration in humans are substantially less than the threshold for renal toxicity in rats (200 micromol/kg). Compound A metabolites quantification may provide a biomarker for compound A exposure and relative metabolism via toxification and detoxication pathways. Compared with previous investigations, relative metabolic flux (fluoromethoxypropanoic acid/mercapturates) through the toxification pathway was sixfold greater in rats than in humans. Species differences in dose and metabolism may influence compound A renal effects.
authors.affiliation: Department of Anesthesiology, University of Washington, Seattle 98195, USA. kharasch@u.washington.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: C
authors.initials: C
authors.lastname: Jubert
mesh_terms: D000107:Acetylation; D000111:Acetylcysteine / Q000378:metabolism* / Q000652:urine; D000328:Adult; D000368:Aged; D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000009:adverse effects / Q000378:metabolism; D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D017558:Elective Surgical Procedures; D004987:Ethers / Q000378:metabolism* / Q000652:urine; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism* / Q000652:urine; D008658:Inactivation, Metabolic; D008297:Male; D008738:Methyl Ethers / Q000009:adverse effects / Q000378:metabolism; D008875:Middle Aged; D011422:Propionates / Q000378:metabolism* / Q000652:urine; D051381:Rats; D000077149:Sevoflurane
chemical_list: C101817:3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid; D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D011422:Propionates; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine