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Metabolism of ketamine stereoisomers by human liver microsomes.

Publication ,  Journal Article
Kharasch, ED; Labroo, R
Published in: Anesthesiology
December 1992

Ketamine is used clinically as a racemic mixture of optical isomers that differ in their analgesic properties and psychomimetic effects. Administered individually, or together as the racemate, ketamine enantiomers differ in their hepatic clearance and duration of anesthetic effect. S(+) ketamine exhibits a greater clearance and faster anesthetic recovery compared to the racemate and a greater clearance compared to R(-) ketamine. Ketamine undergoes extensive hepatic metabolism, primarily via N-demethylation to norketamine, yet little is known about the human metabolism of ketamine enantiomers. The purpose of this investigation therefore was to characterize ketamine racemate and enantiomer metabolism by human liver and to test the hypothesis that differences in hepatic ketamine enantiomer metabolism can account for observed differences in ketamine enantiomer pharmacokinetics. Ketamine N-demethylation by microsomes from three human livers was measured by gas chromatography-mass spectrometry. At ketamine concentrations typically achieved during anesthesia (5 microM), the rate of S(+) ketamine demethylation was 20% greater than that of R(-) ketamine and 10% greater than that of the racemate (P < .05). At all ketamine concentrations, the rate of racemate demethylation was less than the sum of the rates for the individual enantiomers, reflecting a metabolic enantiomeric interactin whereby one ketamine enantiomer inhibits the metabolism of the other enantiomer. N-demethylation of racemic ketamine and each enantiomer was catalyzed by two apparent enzymes, a high affinity-low capacity enzyme (Km1 30-50 microM, Vmax1 2-6 nmoles.min-1 x nmole-1) and a low affinity-high capacity enzyme (Km2 600-800 microM, Vmax2 9-15 nmoles.min-1 x nmole-1).(ABSTRACT TRUNCATED AT 250 WORDS)

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Published In

Anesthesiology

DOI

ISSN

0003-3022

Publication Date

December 1992

Volume

77

Issue

6

Start / End Page

1201 / 1207

Location

United States

Related Subject Headings

  • Stereoisomerism
  • Microsomes, Liver
  • Ketamine
  • In Vitro Techniques
  • Humans
  • Gas Chromatography-Mass Spectrometry
  • Anesthesiology
  • 3202 Clinical sciences
  • 1103 Clinical Sciences
 

Citation

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Kharasch, E. D., & Labroo, R. (1992). Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology, 77(6), 1201–1207. https://doi.org/10.1097/00000542-199212000-00022
Kharasch, E. D., and R. Labroo. “Metabolism of ketamine stereoisomers by human liver microsomes.Anesthesiology 77, no. 6 (December 1992): 1201–7. https://doi.org/10.1097/00000542-199212000-00022.
Kharasch ED, Labroo R. Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology. 1992 Dec;77(6):1201–7.
Kharasch, E. D., and R. Labroo. “Metabolism of ketamine stereoisomers by human liver microsomes.Anesthesiology, vol. 77, no. 6, Dec. 1992, pp. 1201–07. Pubmed, doi:10.1097/00000542-199212000-00022.
Kharasch ED, Labroo R. Metabolism of ketamine stereoisomers by human liver microsomes. Anesthesiology. 1992 Dec;77(6):1201–1207.

Published In

Anesthesiology

DOI

ISSN

0003-3022

Publication Date

December 1992

Volume

77

Issue

6

Start / End Page

1201 / 1207

Location

United States

Related Subject Headings

  • Stereoisomerism
  • Microsomes, Liver
  • Ketamine
  • In Vitro Techniques
  • Humans
  • Gas Chromatography-Mass Spectrometry
  • Anesthesiology
  • 3202 Clinical sciences
  • 1103 Clinical Sciences