CLINICAL SEVOFLURANE METABOLISM AND DISPOSITION .1. SEVOFLURANE AND METABOLITE PHARMACOKINETICS

Background: Sevoflurane has low blood and tissue solubility and is metabolized to free fluoride and hexanfluoroisopropanol (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. Methods: 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. Results: 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 less than or equal to 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 pmol. 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. Conclusions: 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%.