Fluroxene Toxicity Induced by Phenobarbital

Munson, Edwin S.; Malagodi, Marjorie H.; Shields, R.; Tham, Min K.; Fiserova-Bergerova, Vera; Holaday, Duncan A.; Perry, Joel C.; Embro, William J.

doi:10.1097/00132586-197608000-00024

Cited by 2 publications

(5 citation statements)

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“…Similar hepatotoxicity was observed in rats, but the fluroxene anesthesia was not fatal (11). There were no toxic side effects of fluroxene in man (1,8,15) or rhesus monkey (16), with the exception of the four surgical patients mentioned before. Postoperatively these latter patients suffered from nausea, vomiting, fever, jaundice, and hemorrhagic disorder, and histologic examination showed centrolobular necrosis and fatty degeneration of the liver.…”

Section: Metabolites Of Fluroxenesupporting

confidence: 72%

“…TFAA, TFE, and TFEG were also identified in urine of anesthetized rhesus monkeys (16) and man (15). However, TFAA was the major metabolite, and TFE and TFEG were excreted only in traces.…”

Section: Metabolites Of Fluroxenementioning

confidence: 97%

“…Fluroxene anesthesia was fatal in all experimental animals pretreated with phenobarbital (7,11,16). The most remarkable observation is that monkeys (16) and rats (11) tolerated fluroxene anesthesia without any toxic side effect, but none of the animals pretreated with phenobarbital survived a four hour anesthesia.…”

Section: Modification Of Fluroxene Toxicity By Other Drugsmentioning

confidence: 99%

“…Fluroxene is no exception in this respect. [Surprising was the dramatic effect of phenobarbital pretreatment on toxicity and metabolism of tluroxene in rhesus monkey (16). However, similar information on other drugs is not available].…”

Section: Environmental Health Perspectivesmentioning

confidence: 99%

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

Fiserova-Bergerova¹

1977

Environmental Health Perspectives

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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-

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Section: Metabolites Of Fluroxenesupporting

confidence: 72%

“…TFAA, TFE, and TFEG were also identified in urine of anesthetized rhesus monkeys (16) and man (15). However, TFAA was the major metabolite, and TFE and TFEG were excreted only in traces.…”

Section: Metabolites Of Fluroxenementioning

confidence: 97%

Section: Modification Of Fluroxene Toxicity By Other Drugsmentioning

confidence: 99%

Section: Environmental Health Perspectivesmentioning

confidence: 99%

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

Fiserova-Bergerova¹

1977

Environmental Health Perspectives

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“…Recently, female mice have been found to be less susceptible (Gorsky et al 1975). Trifluoroethanol is probably the principal toxic fluroxene metabolite (Johnston & Stevens 1972) but qualitative and quantitative differences between species complicate the extrapolation of these findings to primates and man (Munson et al 1974, Wardell 1973.…”

mentioning

confidence: 99%

Anæsthesia in the Experimental Situation

Green¹

1976

Proceedings of the Royal Society of Medicine

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Fluroxene Toxicity Induced by Phenobarbital

Abstract: Because of reports of fluroxene toxicity in man

Cited by 2 publications

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

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

Anæsthesia in the Experimental Situation

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