Kharasch E D, Karol M D, Lanni C, Sawchuk R
Department of Anesthesiology, University of Washington, Seattle 98195, USA.
Anesthesiology. 1995 Jun;82(6):1369-78. doi: 10.1097/00000542-199506000-00008.
Sevoflurane has low blood and tissue solubility and is metabolized to free fluoride and hexafluoroisopropanol (HFIP). Although sevoflurane uptake and distribution and fluoride formation have been described, the pharmacokinetics of HFIP formation and elimination are incompletely understood. This investigation comprehensively characterized the simultaneous disposition of sevoflurane, fluoride, and HFIP.
Ten patients within 30% of ideal body weight who provided institutional review board-approved informed consent received sevoflurane (2.7% end-tidal, 1.3 MAC) in oxygen for 3 h after propofol induction, after which anesthesia was maintained with propofol, fentanyl, and nitrous oxide. Sevoflurane and unconjugated and total HFIP concentrations in blood were determined during anesthesia and for 8 h thereafter. Plasma and urine fluoride and total HFIP concentrations were measured during and through 96 h after anesthetic administration. Fluoride and HFIP were quantitated using an ion-selective electrode and by gas chromatography, respectively.
The total sevoflurane dose, calculated from the pulmonary uptake rate, was 88.8 +/- 9.1 mmol. Sevoflurane was rapidly metabolized to the primary metabolites fluoride and HFIP, which were eliminated in urine. HFIP circulated in blood primarily as a glucuronide conjugate, with unconjugated HFIP < or = 15% of total HFIP concentrations. In blood, peak unconjugated HFIP concentrations were less than 1% of peak sevoflurane concentrations. Apparent renal fluoride and HFIP clearances (mean +/- SE) were 51.8 +/- 4.5 and 52.6 +/- 6.1 ml/min, and apparent elimination half-lives were 21.4 +/- 2.8 and 20.1 +/- 2.6 h, respectively. Renal HFIP and net fluoride excretion were 4,300 +/- 540 and 3,300 +/- 540 mumol. Compared with the estimated sevoflurane uptake, 4.9 +/- 0.5% of the dose taken up was eliminated in the urine as HFIP. For fluoride, 3.7 +/- 0.4% of the sevoflurane dose taken up was eliminated in the urine, which, because a portion of fluoride is sequestered in bone, corresponded to approximately 5.6% of the sevoflurane dose metabolized to fluoride.
Sevoflurane was rapidly metabolized to fluoride and HFIP, which was rapidly glucuronidated and eliminated in the urine. The overall extent of sevoflurane metabolism was approximately 5%.
七氟烷具有低血液和组织溶解度，且代谢生成游离氟化物和六氟异丙醇（HFIP）。尽管已对七氟烷的摄取、分布及氟化物生成进行了描述，但HFIP生成和消除的药代动力学仍未完全明确。本研究全面表征了七氟烷、氟化物和HFIP的同步处置情况。
10例体重在理想体重30%范围内且提供了经机构审查委员会批准的知情同意书的患者，在丙泊酚诱导后，吸入含2.7%呼气末浓度、1.3倍最低肺泡有效浓度（MAC）的七氟烷与氧气混合气体3小时，之后用丙泊酚、芬太尼和氧化亚氮维持麻醉。在麻醉期间及之后8小时测定血液中七氟烷、未结合及总HFIP浓度。在麻醉给药期间及之后96小时测定血浆和尿液中的氟化物及总HFIP浓度。分别使用离子选择电极和气相色谱法定量氟化物和HFIP。
根据肺摄取率计算，七氟烷总剂量为88.8±9.1 mmol。七氟烷迅速代谢为主要代谢产物氟化物和HFIP，它们经尿液排出。HFIP在血液中主要以葡萄糖醛酸结合物形式循环，未结合的HFIP占总HFIP浓度的≤15%。在血液中，未结合HFIP的峰值浓度低于七氟烷峰值浓度的1%。氟化物和HFIP的表观肾清除率（均值±标准误）分别为51.8±4.5和52.6±6.1 ml/min，表观消除半衰期分别为21.4±2.8和20.1±2.6小时。肾HFIP和净氟化物排泄量分别为4300±540和3300±540 μmol。与估计的七氟烷摄取量相比，摄取剂量的4.9±0.5%以HFIP形式经尿液排出。对于氟化物，摄取的七氟烷剂量的3.7±0.4%经尿液排出，由于一部分氟化物会被骨组织摄取，这相当于代谢生成氟化物的七氟烷剂量的约5.6%。
七氟烷迅速代谢为氟化物和HFIP，HFIP迅速葡萄糖醛酸化并经尿液排出。七氟烷代谢的总体程度约为5%。
