The antitussive effect of dextromethorphan in relation to CYP2D6 activity

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 ad ministration of: (1) Placebo antitussive preceded at 1 h by placebo inhibit or; (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 D EX preceded at 1 h by 50 mg oral quinidine sulphate (QDEX30). Cough frequen cy 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 (DEX:DOR) 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 place bo, DEX30, DEX60 and QDEX30 treatments, respectively. Statistically s ignificant differences in antitussive effect were detected for the contrast s between DEX60/placebo (P<0.001; 95% CI of difference +80, +327) and QDEX3 0/placebo (P<0.001, +88, +336), but not for DEX30/placebo, DEX30/DEX60 or D EX30/QDEX30 (P=0.071, -7, +241; P=0.254, -37, +211; P=0.187, -29, +219, res pectively). Conclusions A significant antitussive effect was demonstrated after 60 mg d extromethorphan and 30 mg dextromethorphan preceded by 50 mg quinidine usin g an induced cough model. However, although the study was powered to detect a 10% difference in cough response, the observed differences for other con trasts were less than 10%, such that it was possible only to imply a dose e ffect (30 vs 60 mg) in the antitussive activity of DEX and enhancement of t his effect by CYP2D6 inhibition.