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Fluroxene toxicity induced by phenobarbital
Abstract:
Because of reports of fluroxene toxicity in man, the effect of phenobarbital treatment on the toxicity and metabolism of fluroxene was studied in 9 rhesus monkeys. Six monkeys that were exposed to a mean calculated alveolar fluroxene concentration of 5.8% for 4-hr periods up to a total of 16 hr showed no evidence of toxicity. Two animals were sacrificed after a single 4-hr exposure to obtain control measures of fluroxene metabolites in tissues. Four monkeys that had previously survived received exposures to fluroxene and 3 monkeys that had no exposure to fluroxene died during fluroxene anesthesia after treatment with phenobarbital (mean time, 3 hr). Toxicity was manifested by arterial hypotension, pulmonary edema, and arterial hypoxemia. Phenobarbital treatment enhanced production of fluroxene metabolites, including the highly toxic trifluoroethanol. Concentrations of trifluoroethanol in mixed-expired gas, blood, and urine, and of total nonvolatile fluorine in blood, urine, and tissues of animals treated with phenobarbital were 2 to 10 times as in control animals. The results suggest that the rhesus monkey is a valuable model for the study of fluroxene pharmacology and that inclusion of an enzyme-inducing challenge in the evaluation of potential toxicity of other anesthetics seems warranted.
Insights
Phenobarbital treatment significantly increased fluroxene toxicity in rhesus monkeys by enhancing the production of toxic metabolites like trifluoroethanol. This highlights the importance of considering enzyme-inducing agents in anesthetic toxicity evaluations.
Area of Science:
- Anesthesiology
- Toxicology
- Pharmacology
Background:
- Reports of fluroxene toxicity in humans necessitate further investigation.
- Understanding anesthetic metabolism and toxicity is crucial for patient safety.
Purpose of the Study:
- To investigate the effect of phenobarbital on fluroxene toxicity and metabolism in rhesus monkeys.
- To evaluate the rhesus monkey as a model for fluroxene pharmacology.
Main Methods:
- Nine rhesus monkeys were used, with some receiving fluroxene exposure and phenobarbital treatment.
- Control groups and treated groups were compared for toxicity signs and metabolite concentrations.
- Fluroxene metabolites, including trifluoroethanol, were quantified in various biological samples.
Main Results:
- Phenobarbital treatment led to the deaths of 3 out of 7 monkeys during fluroxene anesthesia.
- Toxicity manifested as hypotension, pulmonary edema, and hypoxemia.
- Concentrations of trifluoroethanol and total nonvolatile fluorine were 2-10 times higher in phenobarbital-treated animals.
Conclusions:
- Phenobarbital enhances fluroxene metabolism, increasing the production of toxic metabolites and leading to severe toxicity in rhesus monkeys.
- The rhesus monkey serves as a valuable model for studying fluroxene pharmacology.
- Enzyme-inducing challenges should be included in the toxicity evaluation of potential anesthetics.