Compound A Uptake and Metabolism to Mercapturic Acids and 3,3,3-Trifluoro-2-fluoromethoxypropanoic Acid during Low-flow Sevoflurane Anesthesia

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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). Conclusion: 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.