title: Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Noppers
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
authors.forename: Marieke
authors.initials: M
authors.lastname: Niesters
authors.forename: Leon
authors.initials: L
authors.lastname: Aarts
authors.forename: René
authors.initials: R
authors.lastname: Mooren
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.forename: Evan
authors.initials: E
authors.lastname: Kharasch
authors.forename: Elise
authors.initials: E
authors.lastname: Sarton
mesh_terms: D000328:Adult; D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000097:blood; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004347:Drug Interactions / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood*; D008297:Male; D012293:Rifampin / Q000494:pharmacology*; D016037:Single-Blind Method
chemical_list: D000778:Anesthetics, Dissociative; D007649:Ketamine; D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin; C033419:norketamine