Dose-Dependent Metabolism of Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl Ether (Compound A), an Anesthetic Degradation Product, to Mercapturic Acids and 3,3,3-Trifluoro-2-(fluoromethoxy)propanoic Acid in Rats

Abstract

The volatile anesthetic sevoflurane is degraded in anesthesia machines to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), to which humans are exposed. FDVE is metabolized in rats and humans to two alkane and two alkene glutathione S-conjugates that are hydrolyzed to the corresponding cysteine S-conjugates. The latter are N-acetylated to mercapturic acids, or bioactivated by renal cysteine conjugate β-lyase to metabolites which may react with cellular macromolecules or hydrolyze to 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid. FDVE causes nephrotoxicity in rats, which evidence suggests is mediated by renal uptake of FDVE S-conjugates and metabolism by β-lyase. Although pathways of FDVE metabolism have been described qualitatively, the purpose of this investigation was to quantify FDVE metabolism via mercapturic acid and β-lyase pathways. Fischer 344 rats underwent 3-h nose-only exposure to FDVE (0 ± 0, 46 ± 19, 98 ± 7, 150 ± 29, and 220 ± 40 ppm), and urine was collected for 24 h. Urine concentrations of the mercapturates, N-acetyl-S-(1,1,3,3,3-pentafluoro-2-fluoromethoxypropyl)-l-cysteine and N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl)-l-cysteine, the β-lyase-dependent metabolite 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, and its degradation product trifluorolactic acid, were determined by GC/MS. There was dose-dependent urinary excretion of the alkane mercapturate N-acetyl-S-(1,1,3,3,3-pentafluoro-2-fluoromethoxypropyl)-l-cysteine and 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, while excretion of the alkene mercapturate N-acetyl-S-(1-fluoro-2-fluoromethoxy-2-(trifluoromethyl)vinyl)-l-cysteine plateaued at higher FDVE exposures. The alkane:alkene mercapturic acid excretion ratio was between 2:1 and 4:1. Trifluorolactic acid was only rarely observed. Urine excretion of the β-lyase-dependent metabolite 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid was 10-fold greater than that of the combined mercapturates. Results show that FDVE cysteine S-conjugates undergo facile metabolism via renal β-lyase, particularly in comparison with detoxication by mercapturic acid formation. The quantitative assay developed herein may provide a biomarker for FDVE exposure and relative metabolism via toxification and detoxifying pathways, applicable to animal and human investigations.