Fate and toxicity of 2-(fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene (compound A)-derived mercapturates in male, fischer 344 rats

• Published in: Anesthesiology (Philadelphia) Vol. 89; no. 5; pp. 1174 - 1183
• Main Authors: UTTAMSINGH, V, IYER, R. A, BAGGS, R. B, ANDERS, M. W
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 01.11.1998
• Subjects: Acetylcysteine - chemistry; Acyltransferases - metabolism; Anesthetics, Inhalation - pharmacokinetics; Anesthetics, Inhalation - toxicity; Animals; Biological and medical sciences; Biotransformation; Chemical and Drug Induced Liver Injury - pathology; Cytosol - enzymology; Dealkylation; Drug Contamination; Drug toxicity and drugs side effects treatment; Ethers - pharmacokinetics; Ethers - toxicity; Hydrocarbons, Fluorinated - pharmacokinetics; Hydrocarbons, Fluorinated - toxicity; Kidney Diseases - chemically induced; Kidney Diseases - enzymology; Kidney Diseases - pathology; Magnetic Resonance Spectroscopy; Male; Medical sciences; Methyl Ethers - chemistry; Pharmacology. Drug treatments; Rats; Rats, Inbred F344; Sevoflurane; Toxicity: urogenital system; Kidney disease; Volatile compound; Urinary system disease; Rat; Enzyme; Toxicity; Rodentia; Lyases; Aminoacylase; Metabolism; In vitro; Kidney; Sevoflurane; In vivo; Vertebrata; Mammalia; General anesthetic; Animal; Hydrolases; Degradation product; Halogen Organic compounds
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/00000542-199811000-00018

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. 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. 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. 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.