St John's wort greatly decreases the plasma concentrations of oral S-ketamine

Abstract

Ketamine is an intravenous anaesthetic and analgesic agent but it can also be used orally as an adjuvant in the treatment of chronic pain. This study investigated the effect of the herbal antidepressant St John's wort, an inducer of cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics and pharmacodynamics of oral S-ketamine. In a randomized cross-over study with two phases, 12 healthy subjects were pretreated with oral St John's wort or placebo for 14days. On day 14, they were given an oral dose of 0.3mg/kg of S-ketamine. Plasma concentrations of ketamine and norketamine were measured for 24h and pharmacodynamic variables for 12h. St John's wort decreased the mean area under the plasma concentration-time curve (AUC0-∞) of ketamine by 58% (P<0.001) and decreased the peak plasma concentration (Cmax) of ketamine by 66% (P<0.001) when compared with placebo. Mean Cmax of norketamine (the major metabolite of ketamine) was decreased by 23% (P=0.002) and mean AUC0-∞ of norketamine by 18% (P<0.001) by St John's wort. There was a statistically significant linear correlation between the self-reported drug effect and Cmax of ketamine (r=0.55; P<0.01). St John's wort greatly decreased the exposure to oral S-ketamine in healthy volunteers. Although this decrease was not associated with significant changes in the analgesic or behavioural effects of ketamine in the present study, usual doses of S-ketamine may become ineffective if used concomitantly with St John's wort. © 2011 Société Française de Pharmacologie et de Thérapeutique.