THE INFLUENCE OF CYP2D6 POLYMORPHISM AND QUINIDINE ON THE DISPOSITIONAND ANTITUSSIVE EFFECT OF DEXTROMETHORPHAN IN HUMANS

Objectives: We studied the disposition of dextromethorphan in extensiv e and poor metabolizer subjects, as well as the effect of this polymor phism on the antitussive action of dextromethorphan, Methods: Six exte nsive metabolizers were studied on four occasions: (1) after 30 mg dex tromethorphan, (2) after 30 mg dextromethorphan 1 hour before 50 mg qu inidine, (3) after placebo, and (4) after 50 mg quinidine. Six poor me tabolizers were studied on two occasions: (1) after 30 mg dextromethor phan and (2) after placebo, Blood and urine were collected over 168 ho urs and assayed for dextromethorphan, total (conjugated and unconjugat ed) 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 t he plasma concentration-time curve (AUC) was 150-fold greater in the p oor metabolizers than in the extensive metabolizers, and quinidine inc reased the AUC in extensive metabolizers 43-fold. The median dextromet horphan half-life was 19.1 hours in poor metabolizers, 5.6 hours in ex tensive metabolizers given quinidine, and 2.4 hours in extensive metab olizers, For dextrorphan (as total), the AUC was reduced 8.6-fold in p oor metabolizers; quinidine had no effect on the AUC. The median half- life was 10.1 hours in poor metabolizers, 6.6 hours in extensive metab olizers 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 q uinidine, and 970 L/hr in extensive metabolizers. There was a strong ( r(2) = 0.82) and significant (p < 0.01) positive correlation between t he prestudy urinary metabolic ratios and the partial clearances of dex tromethorphan to dextrorphan. There was very large intersubject variab ility in responsiveness to capsaicin. There was no difference in the c apsaicin-induced cough frequency in the three groups. Dextromethorphan had no antitussive effect in this experimental cough model, Conclusio n: The disposition of dextromethorphan was substantially influenced by CYP2D6 status. Capsaicin may not be an ideal agent in experimental co ugh studies.