Enflurane (Ethrane, 2-chloro-1,1,2-trifluoroethyldifluoromethyl ether) is a nonflammable halogenated hydrocarbon that exists as a clear, colorless, odorless to sweet, volatile liquid at ordinary temperature and pressure. Bp: 56.8°C. Density 1.50 g cm-3 at room temperature. Used as an anesthetic.
颜色/状态：
Clear, colorless liquid
气味：
Mild, sweet odor
熔点：
48.5
蒸汽密度：
Relative vapor density (air = 1): 1.9
蒸汽压力：
174.5 mm Hg at 20 °C
大气OH速率常数：
1.19e-14 cm3/molecule*sec
分解：
Hazardous decomposition products formed under fire conditions. - Carbon oxides, hydrogen chloride gas, hydrogen fluoride.
Enflurane is metabolized by the CYP2E1 enzyme in the liver to produce inorganic fluoride ions, the major metabolite of enflurane metabolism. One reference indicates that enflurane is only 2-5% eliminated after oxidative metabolism in the liver, however more recent evidence suggests that about 9% is eliminated via hepatic oxidation.
The toxicity of the chiral fluorinated volatile anesthetics halothane, enflurane, and isoflurane is closely related to their metabolism by hepatic cytochrome P450. Although individual anesthetic enantiomers have been shown to exhibit a difference in anesthetic efficacy, metabolism of anesthetic enantiomers has not been reported. Human liver enflurane metabolism to difluoromethoxydifluoroacetic acid (DFMDFA) and inorganic fluoride is catalyzed in vivo and in vitro by cytochrome P450 2E1. The purpose of this investigation was to characterize enflurane racemate and enantiomer metabolism to test the hypothesis that fluorinated ether anesthetic metabolism by cytochrome P450 2E1 exhibits substrate stereoselectivity. Enflurane metabolism by microsomes from three human livers and by microsomes containing cDNA-expressed human P450 2E1 was measured at saturating enflurane concentrations. DFMDFA was quantitated with gas chromatography-mass spectrometry by detection of the ethanolamide derivative. In microsomes from all three livers, (R)-enflurane metabolism was significantly greater than that of (S)-enflurane, whereas rates of racemic enflurane metabolism were generally between those seen for the R- and S-enantiomers. The ratio of (R)-enflurane to (S)-enflurane metabolism in the three livers studied was 2.1:1, 1.9:1, and 1.4:1. (R)-, (S)-, and racemic enflurane were all metabolized by expressed P450 2E1. The ratio of (R)-enflurane to (S)-enflurane metabolism was 1.9:1. The metabolic enantiomeric selectivity of human liver P450 2E1 for (R)-enflurane suggests that enflurane metabolism by P450 2E1 occurs by direct substrate oxidation, rather than indirectly through the generation of a P450-dependent reactive oxygen species, and supports the hypothesis that the P450 2E1 active site is somewhat restrictive and capable of stereochemical discrimination.
Difluoromethoxydifluoroacetic acid (CHF2OCF2CO2H) has been identified as a metabolite of enflurane (CHF2OCF2CHCIF) in rat liver microsomes in vitro and in human urine by gas chromatography mass spectrometry. The formation of the metabolite in rat liver microsomes was dependent upon the presence of NADPH and O2, and was inhibited when SKF 525-A or CO/O2 (8:2, v/v) were present in the reaction mixture. When the C-H bonds of the CHCIF group of enflurane or of the CHCI group of isoflurane (CHF2OCHCICF3) were replaced with a C-CI bond, virtually no fluoride ion was produced from either derivative in rat liver microsomes. These results indicate that cytochrome P-450 catalyzes the oxidative dehalogenation of CHF2OCF2CHCIF at its CHCIF group to form CHF2OCF2CO2H and chloride and fluoride ions. In contrast, the CHF2 group does not appear to be appreciably susceptible to metabolic oxidative dehalogenation...
Enflurane is a fluorinated volatile anesthetic, mostly eliminated unchanged in exhaled air. About 10% of inhaled enflurane undergoes oxidative metabolism in liver via mixed function oxidase.
Fluorinated ether anesthetic hepatotoxicity and nephrotoxicity are mediated by cytochrome P450-catalyzed oxidative metabolism. Metabolism of the volatile anesthetic enflurane to inorganic fluoride ion by human liver microsomes in vitro is catalyzed predominantly by the cytochrome P450 isoform CYP2E1.
Enflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Enflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. It also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Enflurane also binds to and angonizes the GABA receptor, the large conductance Ca<sup>2+</sup> activated potassium channel, the glycine receptor, and antagonizes the glutamate receptor receptor. These yield a decreased depolarization and therefore, tissue excitability which results in anesthesia.
Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery and anesthesia. Appearance of ALT levels above 10 times the upper limit of normal, however, is distinctly unusual and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from enflurane has been reported but is very rare. The injury resembles halothane hepatotoxicity and is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice 2 to 21 days after surgery and anesthesia. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. The liver injury is often preceded by a day or two of fever and may be accompanied by rash and eosinophilia. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and associated with acute liver failure. A strong risk factor is previous exposure to any of the halogenated anesthetics and particularly a history of halothane hepatitis or unexplained fever and rash after anesthesia with one of these agents.
来源:LiverTox
毒理性
致癌性证据
A4：不能分类为人类致癌物。
A4: Not classifiable as a human carcinogen.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
对人类无致癌性（未列入国际癌症研究机构名录）。
No indication of carcinogenicity to humans (not listed by IARC).
◉ Summary of Use during Lactation:There is no published experience with enflurane during breastfeeding. Because the serum half-life of enflurane in the mother is short and the drug is not expected to be absorbed by the infant, no waiting period or discarding of milk is required. Breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia to nurse. When a combination of anesthetic agents is used for a procedure, follow the recommendations for the most problematic medication used during the procedure. In one study, breastfeeding before general anesthesia induction reduced requirements of sevoflurane and propofol compared to those of nursing mothers whose breastfeeding was withheld or nonnursing women. It is possible that requirements for other anesthetic agents would be affected similarly.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:A randomized study compared the effects of cesarean section using general anesthesia, spinal anesthesia, or epidural anesthesia, to normal vaginal delivery on serum prolactin and oxytocin as well as time to initiation of lactation. General anesthesia was performed using propofol 2 mg/kg and rocuronium 0.6 mg/kg for induction, followed by sevoflurane and rocuronium 0.15 mg/kg as needed. After delivery, patients in all groups received an infusion of oxytocin 30 international units in 1 L of saline, and 0.2 mg of methylergonovine if they were not hypertensive. Fentanyl 1 to 1.5 mcg/kg was administered after delivery to the general anesthesia group. Patients in the general anesthesia group (n = 21) had higher post-procedure prolactin levels and a longer mean time to lactation initiation (25 hours) than in the other groups (10.8 to 11.8 hours). Postpartum oxytocin levels in the nonmedicated vaginal delivery group were higher than in the general and spinal anesthesia groups.
A retrospective study of women in a Turkish hospital who underwent elective cesarean section deliveries compared women who received bupivacaine spinal anesthesia (n = 170) to women who received general anesthesia (n = 78) with propofol for induction, sevoflurane for maintenance and fentanyl after delivery. No differences in breastfeeding rates were seen between the groups at 1 hour and 24 hours postpartum. However, at 6 months postpartum, 67% of women in the general anesthesia group were still breastfeeding compared to 81% in the spinal anesthesia group, which was a statistically significant difference.
来源:Drugs and Lactation Database (LactMed)
吸收、分配和排泄
吸收
恩氟烷通过肺部迅速吸收进入血液循环。其最小肺泡浓度为1.68%。
Enflurane is rapidly absorbed into the circulation through the lungs. The minimum alveolar concentration is oxygen is 1.68%.
来源:DrugBank
吸收、分配和排泄
消除途径
新陈代谢占恩氟烷消除的5-9%，有时会导致肾毒性。通过皮肤的排泄被认为是微量的。
Metabolism accounts for 5-9% of enflurane elimination, sometimes causing nephrotoxicity. Excretion through the skin is believed to be minimal.
来源:DrugBank
吸收、分配和排泄
分布容积
恩氟烷分布到大脑、血液和皮下脂肪。
Enflurane distributes to the brain, blood, and subcutaneous fat.
来源:DrugBank
安全信息
职业暴露限值：
Ceiling: 2 ppm (15.1 mg/m3) [60-minute] [*Note: REL for exposure to waste anesthetic gas.]
Stimulatory effect of anesthetics on dechlorination of carbon tetrachloride in guinea-pig liver microsomes
摘要：
Effects of the anesthetics isoflurane, enflurane, halothane and sevoflurane on the dechlorination of carbon tetrachloride to produce chloroform were investigated using guinea pig liver microsomes. Under anaerobic conditions, chloroform is produced from carbon tetrachloride by the microsomes in the presence of NADPH, and chloroform production from 86 mu M carbon tetrachloride was enhanced to 146%, 133%, 123% and 115% by the addition of isoflurane, enflurane, halothane and sevoflurane, respectively. The half-life of oxidized cytochrome P450 which remained during the reduction by the addition of NADPH was shortened to 51%, 54%, 60% and 80% by isoflurane, enflurane, halothane and sevoflurane, respectively, without alteration of NADPH-cytochrome c reductase activity. These anesthetics hastened the onset of the 445 nm absorption band formation which was shown by microsomes with carbon tetrachloride in the presence of NADPH under anaerobic conditions. These results indicate that the anesthetics isoflurane, enflurane, sevoflurane and halothane stimulate the reduction of cytochrome P450 results in the acceleration of the carbon tetrachloride dechlorination. These results may have implications for other type II drugs that are administered during anesthesia.
Chloropolyfluoro-derivatives of ethyl methyl ether
作者：Paul L. Coe、Roger A. Rowbotham、John Colin Tatlow
DOI：10.1016/s0022-1139(96)03549-x
日期：1997.4
Fluorination of 2-chloroethyl methyl ether by potassium tetrafluorocobaltate at 180–250 °C gave various tri-, tetra-, penta- and hexafluoro(2-chloroethyl methyl) ethers. Cobalttrifluoride afforded the same products in poorer recoveries. Structures were established spectroscopically. Cl2-UV and CHClFCHFOCHF2 gave halogeno-ethers by exchange of Cl for both H and also F.
