The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans

Abstract

Objectives: We studied the disposition of dextromethorphan in extensive and poor metabolizer subjects, as well as the effect of this polymorphism on the antitussive action of dextromethorphan.

Methods: Six extensive metabolizers were studied on four occasions: (1) after 30 mg dextromethorphan, (2) after 30 mg dextromethorphan 1 hour before 50 mg quinidine, (3) after placebo, and (4) after 50 mg quinidine. Six poor metabolizers were studied on two occasions: (1) after 30 mg dextromethorphan and (2) after placebo. Blood and urine were collected over 168 hours and assayed for dextromethorphan, total (conjugated and unconjugated) dextrorphan, 3-methoxymorphinan, and total 3-hydroxymorphinan. On each occasion at each blood sampling time, capsaicin was administered as an aerosol to provoke cough.

Results: Dextromethorphan area under the plasma concentration-time curve (AUC) was 150-fold greater in the poor metabolizers than in the extensive metabolizers, and quinidine increased the AUC in extensive metabolizers 43-fold. The median dextromethorphan half-life was 19.1 hours in poor metabolizers, 5.6 hours in extensive metabolizers given quinidine, and 2.4 hours in extensive metabolizers. For dextrorphan (as total), the AUC was reduced 8.6-fold in poor metabolizers; quinidine had no effect on the AUC. The median half-life was 10.1 hours in poor metabolizers, 6.6 hours in extensive metabolizers given quinidine, and 1.4 hours in extensive metabolizers. The apparent partial clearance of dextromethorphan to dextrorphan was 1.2 L/hr in poor metabolizers, 78.5 L/hr in extensive metabolizers given quinidine, and 970 L/hr in extensive metabolizers. There was a strong (r2 = 0.82) and significant (p < 0.01) positive correlation between the prestudy urinary metabolic ratios and the partial clearances of dextromethorphan to dextrorphan. There was very large intersubject variability in responsiveness to capsaicin. There was no difference in the capsaicin-induced cough frequency in the three groups. Dextromethorphan had no antitussive effect in this experimental cough model.

Conclusion: The disposition of dextromethorphan was substantially influenced by CYP2D6 status. Capsaicin may not be an ideal agent in experimental cough studies.