Evidence for Metabolism of Fluoromethyl 2,2-Difluoro-1-(trifluoromethyl)vinyl Ether (Compound A), a Sevoflurane Degradation Product, by Cysteine Conjugate 详细信息    查看全文

• 作者：Douglas K. Spracklin and Evan D. Kharasch
• 刊名：Chemical Research in Toxicology
• 出版年：1996
• 出版时间：June 1996
• 年：1996
• 卷：9
• 期：4
• 页码：696 - 702
• 全文大小：411K
• 年卷期：v.9,no.4(June 1996)
• ISSN：1520-5010

文摘

The volatile anesthetic sevoflurane is degraded to fluoromethyl2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE), a potent rat nephrotoxin. In ratsin vivo, FDVE undergoesglutathione conjugation and metabolism to cysteine conjugates, whosebioactivation by renalcysteine conjugate ddle">-lyase has been implicated by the protectiveeffects of (aminooxy)aceticacid, an inhibitor of cysteine conjugate ddle">-lyase. Wespecifically tested the hypothesis thatFDVE is metabolized via the ddle">-lyase pathway to yield3,3,3-trifluoro-2-(fluoromethoxy)propanoicacid. Urine of rats administered FDVE (0.3 mmol/kg) was extractedand derivatized withdiazomethane. Headspace GC/MS analysis demonstrated a peak whoseretention time andmass spectrum were identical to those of synthetic methyl3,3,3-trifluoro-2-(fluoromethoxy)propanoate. Pretreatment of rats with (aminooxy)acetic acidsignificantly decreased the amountof 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid detected in theurine of FDVE-treatedanimals. The ¹⁹F NMR spectrum of urine from ratsadministered FDVE was consistent withthe formation of 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid,but could not be differentiatedfrom that of FDVE mercapturates, which are also excreted in urine.These results suggestthat FDVE undergoes biotransformation via the ddle">-lyase pathway andddle">-lyase-catalyzedmetabolism may mediate the nephrotoxicity of thiscompound.