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Clinical isoflurane metabolism by cytochrome P450 2E1.

Publication ,  Journal Article
Kharasch, ED; Hankins, DC; Cox, K
Published in: Anesthesiology
March 1999

BACKGROUND: Some evidence suggests that isoflurane metabolism to trifluoroacetic acid and inorganic fluoride by human liver microsomes in vitro is catalyzed by cytochrome P450 2E1 (CYP2E1). This investigation tested the hypothesis that P450 2E1 predominantly catalyzes human isoflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. METHODS: Twenty-two elective surgery patients who provided institutionally-approved written informed consent were randomized to receive disulfiram (500 mg orally, N = 12) or nothing (controls, N = 10) the evening before surgery. All patients received a standard isoflurane anesthetic (1.5% end-tidal in oxygen) for 8 hr. Urine and plasma trifluoroacetic acid and fluoride concentrations were quantitated in samples obtained for 4 days postoperatively. RESULTS: Patient groups were similar with respect to age, weight, gender, duration of surgery, blood loss, and delivered isoflurane dose, measured by cumulative end-tidal isoflurane concentrations (9.7-10.2 MAC-hr). Postoperative urine excretion of trifluoroacetic acid (days 1-4) and fluoride (days 1-3) was significantly (P<0.05) diminished in disulfiram-treated patients. Cumulative 0-96 hr excretion of trifluoroacetic acid and fluoride in disulfiram-treated patients was 34+/-72 and 270+/-70 micromoles (mean +/- SD), respectively, compared to 440+/-360 and 1500+/-800 micromoles in controls (P<0.05 for both). Disulfiram also abolished the rise in plasma metabolite concentrations. CONCLUSIONS: Disulfiram, a selective inhibitor of human hepatic P450 2E1, prevented 80-90% of isoflurane metabolism. These results suggest that P450 2E1 is the predominant P450 isoform responsible for human clinical isoflurane metabolism in vivo.

Duke Scholars

Published In

Anesthesiology

DOI

ISSN

0003-3022

Publication Date

March 1999

Volume

90

Issue

3

Start / End Page

766 / 771

Location

United States

Related Subject Headings

  • Trifluoroacetic Acid
  • Middle Aged
  • Male
  • Isoflurane
  • Humans
  • Female
  • Enzyme Inhibitors
  • Disulfiram
  • Cytochrome P-450 CYP2E1 Inhibitors
  • Cytochrome P-450 CYP2E1
 

Citation

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Kharasch, E. D., Hankins, D. C., & Cox, K. (1999). Clinical isoflurane metabolism by cytochrome P450 2E1. Anesthesiology, 90(3), 766–771. https://doi.org/10.1097/00000542-199903000-00019
Kharasch, E. D., D. C. Hankins, and K. Cox. “Clinical isoflurane metabolism by cytochrome P450 2E1.Anesthesiology 90, no. 3 (March 1999): 766–71. https://doi.org/10.1097/00000542-199903000-00019.
Kharasch ED, Hankins DC, Cox K. Clinical isoflurane metabolism by cytochrome P450 2E1. Anesthesiology. 1999 Mar;90(3):766–71.
Kharasch, E. D., et al. “Clinical isoflurane metabolism by cytochrome P450 2E1.Anesthesiology, vol. 90, no. 3, Mar. 1999, pp. 766–71. Pubmed, doi:10.1097/00000542-199903000-00019.
Kharasch ED, Hankins DC, Cox K. Clinical isoflurane metabolism by cytochrome P450 2E1. Anesthesiology. 1999 Mar;90(3):766–771.

Published In

Anesthesiology

DOI

ISSN

0003-3022

Publication Date

March 1999

Volume

90

Issue

3

Start / End Page

766 / 771

Location

United States

Related Subject Headings

  • Trifluoroacetic Acid
  • Middle Aged
  • Male
  • Isoflurane
  • Humans
  • Female
  • Enzyme Inhibitors
  • Disulfiram
  • Cytochrome P-450 CYP2E1 Inhibitors
  • Cytochrome P-450 CYP2E1