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)-1,1,3,3,3-tetrafluoro-1-propenyl] -N-acetyl-L-cysteine (compound 5). These experiments were designed to examine the fate and nephrotoxity 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 make Fischer 344 rats. The metabolism of the deuterated analogs of compounds 3 and 5, [acetyl-(2) H3]S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L-cysteine (compound 3-d3) and [acetyl-2 H3]S[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-profenyl]-N-acetyl-cysteine (compound 5-d3), respectively, was measured.Results
Compounds 5, but not compound 3, was hydrolyzed by human and rat kidney cytosols and by acylases I and III.19 F 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- thiazole-4-carboxylic acid were detected in urine. Compounds 5 (250 [micro sign]M/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 mildy nephrotoxic. These results indicate that compound A-derived mercapturate formation constitutes a detoxication pathway for compound A.