Exposure to oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine

Clin Pharmacol Ther. 2011 Aug;90(2):296-302. doi: 10.1038/clpt.2011.140. Epub 2011 Jun 29.

Abstract

This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Anesthetics, Dissociative / pharmacokinetics
  • Anesthetics, Dissociative / pharmacology
  • Antifungal Agents / pharmacology
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors
  • Double-Blind Method
  • Drug Interactions
  • Female
  • Humans
  • Itraconazole / pharmacology*
  • Ketamine / analogs & derivatives
  • Ketamine / pharmacokinetics*
  • Ketamine / pharmacology
  • Male
  • Oxidoreductases, N-Demethylating / antagonists & inhibitors
  • Oxidoreductases, N-Demethylating / metabolism*
  • Platelet Aggregation Inhibitors / pharmacology
  • Ticlopidine / pharmacology*
  • Young Adult

Substances

  • Anesthetics, Dissociative
  • Antifungal Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Platelet Aggregation Inhibitors
  • Itraconazole
  • Ketamine
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Ticlopidine
  • norketamine