Abstract
Objective
Variation in the activity of cytochrome P450 2D6 (CYP2D6) affects the pharmacokinetics and effectiveness of dextromethorphan (DM), because it controls the production of dextrorphan, an active metabolite, with higher affinity for the NMDA receptor than the parent compound. This study examined whether pharmacological inhibition of CYP2D6 activity with quinidine would mimic the genetic mutation and thus also alter the psychoactive effects of DM.
Methods
In a singleโblind, withinโsubjects study, eight healthy volunteers (all homozygous for the wild type allele for CYP2D6) received placebo and varying doses of DM, both with and without quinidine preโtreatment. Pharmacokinetic and pharmacodynamic measures were assessed at baseline and every hour postโdrug for 6โh.
Results
Compared to the no quinidine condition, quinidine preโtreatment decreased the area under the doseโresponse curve on subjective measures of positively reinforcing effects (e.g., euphoria, pโ<โ0.04; drug liking, pโ<โ0.05), and was significantly greater for measures of dysphoria (e.g., unpleasantness, pโ<โ0.02). These changes corresponded to increased DM and decreased dextrorphan plasma concentrations.
Conclusions
Compared to DM alone, quinidine preโtreatment inhibited DM metabolism and changed its subjective effects, demonstrating that the psychoactive properties of DM are a function of drug metabolism. These results demonstrate the relationship between CYP2D6 activity, plasma drug levels, and psychoactive drug effects, and have implications for both the abuse liability and therapeutic utility of DM. Copyright ยฉ 2009 John Wiley & Sons, Ltd.