Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine

Eur J Pain. 2010 Jul;14(6):625-9. doi: 10.1016/j.ejpain.2009.10.003. Epub 2009 Nov 7.


Background: Oral ketamine is used as an adjuvant in the treatment of refractory neuropathic and cancer-related pain. Drug interactions may alter the analgesic or other effects of ketamine.

Aim and methods: The aim of the study was to investigate the effect of cytochrome P450 3A enzyme inhibition with clarithromycin on the pharmacokinetics and pharmacodynamics of oral S-ketamine in a randomized controlled cross-over study with two phases. Ten healthy subjects were pre-treated with oral clarithromycin or placebo for 4 days. On day 4, they ingested an oral dose of 0.2mg/kg of S-ketamine syrup. Plasma concentrations of ketamine and norketamine were measured for 24h. Analgesic effects were evaluated in a cold pressor test and psychomotor effects were followed for 12h.

Results: Clarithromycin increased the mean C(max) of ketamine by 3.6-fold (p<0.001) and the mean AUC(0-infinity) of ketamine by 2.6-fold (p=0.001). The relative amount of the CYP3A dependent metabolite norketamine was decreased by 54% by clarithromycin (p=0.004). Self-rated drug effect of S-ketamine was enhanced by clarithromycin (p<0.05) but other behavioral effects or cold pain scores were not affected.

Conclusions: Clarithromycin strongly increases plasma concentrations of oral S-ketamine probably by inhibiting its CYP3A-mediated N-demethylation. This increase is reflected as modest changes in behavioral effects of oral S-ketamine.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics / administration & dosage
  • Analgesics / blood
  • Analgesics / pharmacokinetics
  • Area Under Curve
  • Clarithromycin / administration & dosage*
  • Clarithromycin / blood
  • Cross-Over Studies
  • Drug Interactions
  • Female
  • Humans
  • Ketamine / administration & dosage*
  • Ketamine / blood
  • Ketamine / pharmacokinetics*
  • Male
  • Pain Measurement / drug effects*
  • Protein Synthesis Inhibitors / administration & dosage
  • Protein Synthesis Inhibitors / blood


  • Analgesics
  • Protein Synthesis Inhibitors
  • Ketamine
  • Clarithromycin