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Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration.

Publication ,  Journal Article
Noppers, I; Olofsen, E; Niesters, M; Aarts, L; Mooren, R; Dahan, A; Kharasch, E; Sarton, E
Published in: Anesthesiology
June 2011

BACKGROUND: Low-dose ketamine is used as analgesic for acute and chronic pain. It is metabolized in the liver to norketamine via cytochrome P450 (CYP) enzymes. There are few human data on the involvement of CYP enzymes on the elimination of norketamine and its possible contribution to analgesic effect. The aim of this study was to investigate the effect of CYP enzyme induction by rifampicin on the pharmacokinetics of S-ketamine and its major metabolite, S-norketamine, in healthy volunteers. METHODS: Twenty healthy male subjects received 20 mg/70 kg/h (n = 10) or 40 mg/70 kg/h (n = 10) intravenous S-ketamine for 2 h after either 5 days oral rifampicin (once daily 600 mg) or placebo treatment. During and 3 h after drug infusion, arterial plasma concentrations of S-ketamine and S-norketamine were obtained at regular intervals. The data were analyzed with a compartmental pharmacokinetic model consisting of three compartments for S-ketamine, three sequential metabolism compartments, and two S-norketamine compartments using the statistical package NONMEM® 7 (ICON Development Solutions, Ellicott City, MD). RESULTS: Rifampicin caused a 10% and 50% reduction in the area-under-the-curve of the plasma concentrations of S-ketamine and S-norketamine, respectively. The compartmental analysis indicated a 13% and 200% increase in S-ketamine and S-norketamine elimination from their respective central compartments by rifampicin. CONCLUSIONS: : A novel observation is the large effect of rifampicin on S-norketamine concentrations and indicates that rifampicin induces the elimination of S-ketamine's metabolite, S-norketamine, probably via induction of the CYP3A4 and/or CYP2B6 enzymes.

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Published In

Anesthesiology

DOI

EISSN

1528-1175

Publication Date

June 2011

Volume

114

Issue

6

Start / End Page

1435 / 1445

Location

United States

Related Subject Headings

  • Single-Blind Method
  • Rifampin
  • Male
  • Ketamine
  • Infusions, Intravenous
  • Humans
  • Enzyme Induction
  • Drug Interactions
  • Cytochrome P-450 Enzyme System
  • Cross-Over Studies
 

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Noppers, I., Olofsen, E., Niesters, M., Aarts, L., Mooren, R., Dahan, A., … Sarton, E. (2011). Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration. Anesthesiology, 114(6), 1435–1445. https://doi.org/10.1097/ALN.0b013e318218a881
Noppers, Ingeborg, Erik Olofsen, Marieke Niesters, Leon Aarts, René Mooren, Albert Dahan, Evan Kharasch, and Elise Sarton. “Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration.Anesthesiology 114, no. 6 (June 2011): 1435–45. https://doi.org/10.1097/ALN.0b013e318218a881.
Noppers I, Olofsen E, Niesters M, Aarts L, Mooren R, Dahan A, et al. Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration. Anesthesiology. 2011 Jun;114(6):1435–45.
Noppers, Ingeborg, et al. “Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration.Anesthesiology, vol. 114, no. 6, June 2011, pp. 1435–45. Pubmed, doi:10.1097/ALN.0b013e318218a881.
Noppers I, Olofsen E, Niesters M, Aarts L, Mooren R, Dahan A, Kharasch E, Sarton E. Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration. Anesthesiology. 2011 Jun;114(6):1435–1445.

Published In

Anesthesiology

DOI

EISSN

1528-1175

Publication Date

June 2011

Volume

114

Issue

6

Start / End Page

1435 / 1445

Location

United States

Related Subject Headings

  • Single-Blind Method
  • Rifampin
  • Male
  • Ketamine
  • Infusions, Intravenous
  • Humans
  • Enzyme Induction
  • Drug Interactions
  • Cytochrome P-450 Enzyme System
  • Cross-Over Studies