The antitussive effect of dextromethorphan in relation to CYP2D6 activity

Abstract

Aims To test the hypothesis that inhibition of cytochrome P450 2D6 (CYP2D6) by quinidine increases the antitussive effect of dextromethorphan (DEX) in an induced cough model. Methods Twenty-two healthy extensive metaboliser phenotypes for CYP2D6 were studied according to a double-blind, randomised cross-over design after administration of : (1) Placebo antitussive preceded at 1 h by placebo inhibitor; (2) 30 mg oral DEX preceded at 1 h by placebo inhibitor (DEX30); (3) 60 mg oral DEX preceded at 1 h by placebo inhibitor (DEX60); (4) 30 mg oral DEX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequency following inhalation of 10% citric acid was measured at baseline and at intervals up to 12 h. Plasma concentrations of DEX and its metabolites were measured up to 96 h by h.p.l.c. Results Inhibition of CYP2D6 by quinidine caused a significant increase in the mean ratio of DEX to dextrorphan (DEX5DOR) plasma AUC(96) (0.04 vs 1.81, P<0.001). The mean (±s.d.) decrements in cough frequency below baseline over 12 h (AUEC) were: 8% (11), 17% (14.5), 25% (16.2) and 25% (16.9) for placebo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically significant differences in antitussive effect were detected for the contrasts between DEX60/placebo ( P<0.001; 95% CI of difference +80, +327) and QDEX30/placebo ( P<0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or DEX30/QDEX30 ( P=0.071, −7, +241; P=0.254, −37, +211; P=0.187, −29, +219, respectively). Conclusions A significant antitussive effect was demonstrated after 60 mg dextromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine using an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other contrasts were less than 10%, such that it was possible only to imply a dose effect (30 vs 60 mg ) in the antitussive activity of DEX and enhancement of this effect by CYP2D6 inhibition.Keywords: antitussive effect, CYP2D6, dextromethorphan, genetic polymorphism tion [8]. N-demethylation to 3-methoxymorphinan also Introduction occurs, largely by CYP3A4 but with contributions from CYPs 2C9 and 2C19 [9][10][11][12]. Both dextrorphan Dextromethorphan, a codeine analogue devoid of opiate side-effects, is widely available over-the-counter as a and 3-methoxymorphinan are further metabolized to 3-hydroxymorphinan, by CYPs 3A4 and 2D6, respectcough suppressant. Its efficacy has been confirmed in both clinical cough [1][2][3][4][5] and in experimental cough ively [13]. It is well established that the overall disposition of dextromethorphan is highly dependent upon CYP2D6 challenge studies [6, 7]. Metabolism of dextromethorphan is largely by CYP2D6-mediated O-demethylation to activity, which varies widely due to genetic polymorphism, and which can be inhibited selectively and dextrorphan, which then undergoes glucuronide formasignificantly by a small dose of quinidine [14][15][16].

The Placebo Response to Citric Acid-induced Cough: Pharmacodynamics and Gender Differences

“…There was a 1 h lag time before the onset of placebo action. The estimated Cough challenge overall effect, as measured by AUEC (area under As explained in our previous report, 20 a 10% w/v the effect-time curve), was 15.9 (coughs.h). Table 1 solution of citric acid was prepared by diluting a stock indicates the characteristics of the models used and 1 M solution with 0.9% saline, and 3 ml was placed their respective AIC values.…”

Physiologically based modelling of inhibition of metabolism and assessment of the relative potency of drug and metabolite: dextromethorphan vs. dextrorphan using quinidine inhibition

“…However, a number of experimental approaches are possible involving deliberate or natural perturbation of the drug/metabolite ratio. These include administration of the metabolite alone [1], inhibition of the metabolic pathway that is responsible for the formation of the metabolite [2, 3], and investigation of pharmacological effect in subpopulations who are polymorphic with respect to the biotransformation pathway that produces the active metabolite [4, 5]. PK–PD modelling can be used as a complementary step in all of the above methods [6–8], where inter‐ or intra‐individual differences in plasma concentration–time profiles between the parent drug and its metabolite are used to quantify the effect of each chemical moiety.…”

Incorporating In Vitro Information on Drug Metabolism Into Clinical Trial Simulations to Assess the Effect of CYP2D6 Polymorphism on Pharmacokinetics and Pharmacodynamics: Dextromethorphan as a Model Application

“…Capon et al 20 were successful in demonstrating a difference in the AUC of dextromethorphan between 6 EM and 6 PM subjects but failed to detect a significant difference in antitussive response between these groups or between EMs and the same individuals phenocopied to PMs by administration of quinidine. Abdul Manap et al 21 carried out a similar study with a larger size of 22 EM subjects who were phenocopied to PMs and also detected a significant phenotypic difference in PK but not PD. The present study predicts that these 2 studies had powers of 95% and 100%, respectively, to differentiate differences in the PK of dextromethorphan between EMs and PMs but powers of only 10% and 15%, respectively to detect differences in PD.…”

“… The power (%) of simulated studies to show significant differences in AUC and AUEC between CYP2D6 phenotypes versus the number of subjects in each study arm (n). The arrows indicate the size of published studies: (a) Capon et al 20 and (b) Abdul Manap et al 21 …”