Fate and toxicity of 2-(fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A)-derived mercapturates in male, Fischer 344 rats.
BACKGROUND
2-(Fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A) is formed in the anesthesia circuit by the degradation of sevoflurane. Compound A is nephrotoxic in rats and undergoes metabolism by the mercapturic acid pathway in rats and humans to yield the mercapturates S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L -cysteine (compound 3) and S-[2(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl-L-cys teine (compound 5). These experiments were designed to examine the fate and nephrotoxicity of compound A-derived mercapturates in rats.


METHODS
The deacetylation of compounds 3 and 5 by human and rat kidney cytosol and with purified acylases I and III was measured, and their nephrotoxicity was studied in male Fischer 344 rats. The metabolism of the deuterated analogs of compounds 3 and 5, [acetyl-2H3]S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl ]-N-acetyl-L-cysteine (compound 3-d3) and [acetyl-2H3]S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N -acetyl-L-cysteine (compound 5-d3), respectively, was measured.


RESULTS
Compound 5, but not compound 3, was hydrolyzed by human and rat kidney cytosols and by acylases I and III. 19F nuclear magnetic resonance spectroscopic analysis showed no urinary metabolites of compound 3, but unchanged compound 5 and its metabolites 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 2-[1-(fluoromethoxy)-2,2,2-trifluoroethyl]-4,5-dihydro-1,3-thiazol e-4-carboxylic acid were detected in urine. Compound 5 (250 microM/kg) produced clinical chemical and morphologic evidence of renal injury in two of three animals studied.


CONCLUSIONS
Compounds 3 and 5 underwent little metabolism. Compound 5, but not compound 3, was mildly nephrotoxic. These results indicate that compound A-derived mercapturate formation constitutes a detoxication pathway for compound A.
Uttamsingh
V
V
Department of Pharmacology and Physiology, University of Rochester, New York 14642, USA.
Iyer
R A
RA
Baggs
R B
RB
Anders
M W
MW
D000111:Acetylcysteine / Q000737:chemistry*; D000217:Acyltransferases / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D003600:Cytosol / Q000201:enzymology; D003640:Dealkylation; D004340:Drug Contamination; D004987:Ethers / Q000493:pharmacokinetics* / Q000633:toxicity; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics* / Q000633:toxicity; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008738:Methyl Ethers / Q000737:chemistry*; D051381:Rats; D011916:Rats, Inbred F344; D000077149:Sevoflurane
D018685:Anesthetics, Inhalation; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D008738:Methyl Ethers; D000077149:Sevoflurane; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; D000217:Acyltransferases; D000111:Acetylcysteine