Sevoflurane is metabolized to hexafluoroisopropanol by cytochrome P450 2E1 in a reaction that promotes the release of inorganic fluoride and carbon dioxide. Hexafluoroisopropanol is rapidly conjugated with glucuronic acid and eliminated in urine. _In vivo_ metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized. In most cases, inorganic fluoride reaches its highest concentration within 2 hours of the end of sevoflurane anesthesia, and returns to baseline levels within 48 hours. Sevoflurane metabolism may be induced by chronic exposure to isoniazid and ethanol, and it has been shown that barbiturates do not affect it.
Renal and hepatic toxicity of the fluorinated ether volatile anesthetics is caused by biotransformation to toxic metabolites. Metabolism also contributes significantly to the elimination pharmacokinetics of some volatile agents. Although innumerable studies have explored anesthetic metabolism in animals, there is little information on human volatile anesthetic metabolism with respect to comparative rates or the identity of the enzymes responsible for defluorination. The first purpose of this investigation was to compare the metabolism of the fluorinated ether anesthetics by human liver microsomes. The second purpose was to test the hypothesis that cytochrome P450 2E1 is the specific P450 isoform responsible for volatile anesthetic defluorination in humans. Microsomes were prepared from human livers. Anesthetic metabolism in microsomal incubations was measured by fluoride production. The strategy for evaluating the role of P450 2E1 in anesthetic defluorination involved three approaches: for a series of 12 human livers, correlation of microsomal defluorination rate with microsomal P450 2E1 content (measured by Western blot analysis), correlation of defluorination rate with microsomal P450 2E1 catalytic activity using marker substrates (para-nitrophenol hydroxylation and chlorzoxazone 6-hydroxylation), and chemical inhibition by P450 isoform-selective inhibitors. The rank order of anesthetic metabolism, assessed by fluoride production at saturating substrate concentrations, was methoxyflurane > sevoflurane > enflurane > isoflurane > desflurane > 0. There was a significant linear correlation of sevoflurane and methoxyflurane defluorination with antigenic P450 2E1 content (r = 0.98 and r = 0.72, respectively), but not with either P450 1A2 or P450 3A3/4. Comparison of anesthetic defluorination with either para-nitrophenol or chlorzoxazone hydroxylation showed a significant correlation for sevoflurane (r = 0.93, r = 0.95) and methoxyflurane (r = 0.78, r = 0.66). Sevoflurane defluorination was also highly correlated with that of enflurane (r = 0.93), which is known to be metabolized by human P450 2E1. Diethyldithiocarbamate, a selective inhibitor of P450 2E1, produced a concentration-dependent inhibition of sevoflurane, methoxyflurane, and isoflurane defluorination. No other isoform-selective inhibitor diminished the defluorination of sevoflurane, whereas methoxyflurane defluorination was inhibited by the selective P450 inhibitors furafylline (P450 1A2), sulfaphenazole (P450 2C9/10), and quinidine (P450 2D6) but to a much lesser extent than by diethyldithiocarbamate. These results demonstrate that cytochrome P450 2E1 is the principal, if not sole human liver microsomal enzyme catalyzing the defluorination of sevoflurane. P450 2E1 is the principal, but not exclusive enzyme responsible for the metabolism of methoxyflurane, which also appears to be catalyzed by P450s 1A2, 2C9/10, and 2D6. The data also suggest that P450 2E1 is responsible for a significant fraction of isoflurane metabolism. Identification of P450 2E1 as the major anesthetic metabolizing enzyme in humans provides a mechanistic understanding of clinical fluorinated ether anesthetic metabolism and toxicity.
Sevoflurane, USP is metabolized to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Fluoride ion concentrations are influenced by the duration of anesthesia and the concentration of sevoflurane, USP. Once formed, HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane, USP have been identified. In humans, the fluoride ion half-life was prolonged in patients with renal impairment, but human clinical trials contained no reports of toxicity associated with elevated fluoride ion levels.
Cytochrome P450 2E1 is the principal isoform identified for sevoflurane metabolism and this may be induced by chronic exposure to isoniazid and ethanol. This is similar to the metabolism of isoflurane and enflurane and is distinct from that of methoxyflurane which is metabolized via a variety of cytochrome P450 isoforms. The metabolism of sevoflurane is not inducible by barbiturates. As shown in Figure 5, inorganic fluoride concentrations peak within 2 hours of the end of sevoflurane anesthesia and return to baseline concentrations within 48 hours post-anesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism.
Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. In vivo metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized.
Sevoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Sevoflurane 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 and also binds to the GABA receptor, the large conductance Ca<sup>2+</sup> activated potassium channel, the glutamate receptor, and the glycine receptor.
Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery. 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 sevoflurane is very rare, only isolated case reports having been published. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 21 days of surgery. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. Jaundice is usually 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. The differential diagnosis of acute liver injury after surgery and anesthesia is sometimes difficult, and a clinical picture similar to sevoflurane induced hepatitis can be caused by shock or ischemia, sepsis, other idiosyncratic forms of drug induced liver injury and acute viral or herpes hepatitis.
来源:LiverTox
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
◉ Summary of Use during Lactation:There is little published experience with sevoflurane during breastfeeding. Because the serum half-life of sevoflurane in the mother 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. General anesthesia for cesarean section using sevoflurane as a component may delay the onset of lactation. 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.
◉ 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)
毒理性
暴露途径
该物质可以通过吸入其蒸汽和摄入进入人体。
The substance can be absorbed into the body by inhalation of its vapour and by ingestion.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
Sevoflurane is rapidly absorbed into circulation through the lungs; however, solubility in the blood is low (blood/gas partition coefficient at 37°C ranges from 0.63 to 0.69). Therefore, a minimal amount of sevoflurane needs to be dissolved in blood in order to induce anesthesia.
The low solubility of sevoflurane facilitates its rapid elimination through the lungs, where 95% to 98% of this anesthetic is eliminated. Up to 3.5% of the sevoflurane dose appears in urine as inorganic fluoride, and as much as 50% of fluoride clearance is nonrenal (fluoride taken up into bone).
Patients given low-flow sevoflurane anesthesia during maxillofacial surgery (n=16) had a peripheral volume of distribution of 1634 ml<sub>vapour</sub>/kg<sub>bw</sub> and a total volume of distribution of 1748 ml<sub>vapour</sub>/kg<sub>bw</sub>.
In patients given low-flow sevoflurane anaesthesia during maxillofacial surgery (n=16), the transport clearance from the central to the peripheral compartment was 13.0 ml<sub>vapour</sub>/kg<sub>bw</sub>⋅min.
Up to 3.5% of the sevoflurane dose appears in the urine as inorganic fluoride. Studies on fluoride indicate that up to 50% of fluoride clearance is nonrenal (via fluoride being taken up into bone).
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.
Activation of Alkyl C–F Bonds by B(C<sub>6</sub>F<sub>5</sub>)<sub>3</sub>: Stoichiometric and Catalytic Transformations
作者：Christopher B. Caputo、Douglas W. Stephan
DOI：10.1021/om200885c
日期：2012.1.9
The Lewis acid B(C6F5)3 is shown to activate a series of alkyl fluorides. In stoichiometric reactions, treatment of sterically demanding phosphines with B(C6F5)3/alkyl fluorides gives phosphonium fluoroborate salts while treatment of B(C6F5)3/alkyl fluorides with the salts [tBu3PX][XB(C6F5)3] (X = H, PhS) gives the alkane and the salt byproduct [tBu3PX][FB(C6F5)3]. These fluoroalkanes are also catalytically
显示路易斯酸B（C 6 F 5）3活化一系列烷基氟化物。在化学计量反应中，用B（C 6 F 5）3 /烷基氟化物处理空间要求的膦，得到氟硼酸phospho盐，而用盐[ t Bu 3 PX] [XB]处理B（C 6 F 5）3 /烷基氟化物。（C 6 F 5）3 ]（X = H，PhS）得到烷烃和盐副产物[ t Bu 3 PX] [FB（C 6 F 5）3]。通过使用B（C 6 F 5）3作为催化剂，通过氟代烷烃与Et 3 SiH的反应，这些氟代烷烃也被催化转化为相应的烷烃。
A method for preparing a fluorinated vinyl ether compound comprising reacting a fluorinated ether substrate having (i) a hydrogen atom on a carbon atom that is alpha to an etheric oxygen and (ii) a fluorine atom on a carbon atom that is beta to the etheric oxygen, with an organolithium base to provide a reaction product comprising a fluorinated vinyl ether compound.
Diisopropylethylamine mono(hydrogen fluoride) for nucleophilic fluorination of sensitive substrates: synthesis of sevoflurane
作者：Linas V Kudzma、Chialang G Huang、Ralph A Lessor、Leonid A Rozov、Syeda Afrin、Florida Kallashi、Conor McCutcheon、Keith Ramig
DOI：10.1016/s0022-1139(01)00396-7
日期：2001.9
fluoride) (7), is shown to be an effective and selective nucleophilic fluorinating reagent when applied to halogen-exchange reactions of chloromethyl ethers, in particular the conversion of 1,1,1,3,3,3-hexafluoroisopropyl chloromethyl ether (3) to the volatile anesthetic sevoflurane (1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether). The amine portion of the reagent does not react with the starting
Hexafluoroisopropanol (CF3CHOHCF3) is manufactured in two steps from monochloromalonic acid or monochlomalonic acid esters by a reaction with a fluorinating agent, notably SF4, to form CF3CHClCF3 which is hydrolyzed to form CF3CHOHCF3.
The hexafluoroisopropanol can be used as such, or, preferably, it is further reacted to form Sevoflurane, an anesthetic.
Compounds of the formula CF3-CH(OY)-CF3 wherein Y is OTs, OMe, OTf or OTMS are also described.
