Cysteine conjugate beta-lyase-dependent metabolism of compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluoro-1-propene) in human subjects anesthetized with sevoflurane and in rats given compound A.
BACKGROUND
Sevoflurane undergoes Baralyme- or soda lime-catalyzed degradation in the anesthesia circuit to yield compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluroro-1-propene), which is nephrotoxic in rats and undergoes metabolism via the cysteine conjugate beta-lyase pathway in those animals. The objective of these experiments was to test the hypothesis that compound A undergoes beta-lyase-dependent metabolism in humans.


METHODS
Human volunteers were anesthetized with sevoflurane (1.25 minimum alveolar concentration, 3%, 2 l/min, 8 h) and thereby exposed to compound A. Urine was collected at 24-h intervals for 72 h after anesthesia. Rats, which served as a positive control, were given compound A intraperitoneally, and urine was collected for 24 h afterward. Human and rat urine samples were analyzed by 19F nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry for the presence of compound A metabolites.


RESULTS
Analysis of human and rat urine showed the presence of the compound A metabolites S-[2(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L- cysteine, (E)- and (Z)-S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl- L-cysteine, 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid, 3,3,3-trifluorolactic acid, and inorganic fluoride. The presence of 2-(fluoromethoxy)3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid in human urine was confirmed by gas chromatography-mass spectrometry.


CONCLUSIONS
The formation of compound A-derived mercapturates shows that compound A undergoes glutathione S-conjugate formation. The identification of 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid in the urine of humans anesthetized with sevoflurane shows that compound A undergoes beta-lyase-dependent metabolism. Metabolite formation was qualitatively similar in both human volunteers anesthetized with sevoflurane, and thereby exposed to compound A, and in rats given compound A, indicating that compound A is metabolized by the beta-lyase pathway in both species.
Iyer
R A
RA
Department of Pharmacology and Physiology, University of Rochester, New York 14642, USA.
Frink
E J
EJ
Ebert
T J
TJ
Anders
M W
MW
D018685:Anesthetics, Inhalation / Q000378:metabolism*; D000818:Animals; D013437:Carbon-Sulfur Lyases; D004987:Ethers / Q000378:metabolism* / Q000652:urine; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism* / Q000652:urine; D008190:Lyases / Q000378:metabolism*; D008738:Methyl Ethers / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D051381:Rats; D011916:Rats, Inbred F344; D000077149:Sevoflurane; D014838:Volunteers
D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D008190:Lyases; D013437:Carbon-Sulfur Lyases; C019969:S-alkylcysteine lyase