Metabolism and Toxicity of 2,2,2-Trifluoroethyl Vinyl Ether

Abstract

A review on metabolism and toxicity of the fluorinated anesthetic agent, fluroxene, is presented. Fluroxene anesthesia is nontoxic to man but fatal to many experimental animals. The fluroxene molecule (2,2,2-trifluoroethyl vinyl ether) is composed of two moieties; both are toxic as a result of their metabolism: the vinyl moiety destroys heme of cytochrome P-450 while being metabolized to the final product, CO2. The trifluoroethyl moiety is oxidized to trifluoroethanol (TFE) and trifluoroacetic acid (TFAA), and the acute toxicity of fluroxene is related to this pathway. The ratio of metabolites (TFAA to TFE) excreted by different species exposed to fluroxene varies; whenever highly toxic TFE is the major metabolite, fluroxene toxicity is high (rodents, dogs, phenobarbital pretreated monkeys), whenever TFAA is the major metabolite (man, monkey) fluroxene is not toxic. Toxicity in different species also correlates with the extent of glutathione depletion following fluroxene exposure.Fluroxene metabolism and toxicity are modified by drugs metabolized by or affecting the activity of the microsomal cytochrome P-450-system or enzymes involved in ethanol metabolism. The susceptibility of fluroxene to two enzymatic systems which are modified by environmental and genetic factors may explain the large differences in fluroxene toxicity to various species. The fate of one-third of fluroxene administered to man remains unknown.Trifluoroethyl vinyl ether, fluroxene, was introduced in 1953 as the first fluorinated inhalation anesthetic (1), under the trade name Fluoromar. It is slightly flammable, but was considered to be an anesthetic agent of high clinical safety. In 1975, after enflurane had appeared on the market, the manufacture of fluroxene was discontinued. The 22-year history of fluroxene (Table 1) is an interesting one. During this period, fluroxene was found to be toxic to surgical patients in only four cases, and in these four cases other medications were involved (9, 10, 13, 14). As good as this record is, fluroxene would never have been approved for use in humans if it had to undergo present-day testing standards, because it happens to be highly toxic to experimental animals (recognized in 1972) (7) and is extensively metabolized to highly toxic metabolites (discovered in 1967) (5). Metabolites of FluroxeneWhen labeled fluroxene was injected into mice and dogs, trifluoroacetic acid (TFAA) and tri-

In vivo 19F Magnetic Resonance Spectroscopy and Chemical Shift Imaging of Tri-Fluoro-Nitroimidazole as a Potential Hypoxia Reporter in Solid Tumors

“…tissues (blood, muscle, spleen, and kidneys). About the possibility of catabolism of TF-MISO, which could potentially affect its role as a valid hypoxia reporter, we note that the most likely other possible metabolism of TF-MISO could be the cleavage of the trifluoroethoxy group, which in turn would be metabolized to trifluoroacetic acid and rapidly excreted (minutes after injection) through the kidneys (41). As the scanning takes place at least 30 min after injection, the only effect this would have would be a lower target tissue uptake of TF-MISO.…”