Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects

CYP2D6 is polymorphically distributed so that in poor metaboliters enzyme a ctivity is missing. The goal of this study was to compare the pharmacokinet ics and pharmacodynamics of codeine with and without quinidine between Cauc asian and Chinese extensive metabolizers of debrisoquin. Nine Caucasians an d eight Chinese subjects received in random, double blind fashion, on two o ccasions, codeine 120 mg. with placebo or with quinidine 100 mg. Pharmacody namic effects were determined over 6 h, Codeine-apparent clearance and part ial metabolic clearance by O-demethylation were significantly greater in th e Caucasian than in the Chinese subjects (1939 +/- 175 ml/min versus 1301 /- 193 ml/min, p < .03 and 162.7 +/- 36.6 ml/min versus 52.7 +/- 12.7 ml/mi n, p < .02, respectively). Codeine's respiratory effects (except on resting ventilation) were significantly greater in the Caucasian than in the Chine se subjects (p < .05), but no interethnic differences were noted in codeine 's effect on the digit symbol substitution test and pupillary ratio. No mor phine or morphine metabolites were detected in plasma when codeine was coad ministered with quinidine. Codeine O-demethylation was significantly reduce d after quinidine in both ethnic groups; however, the absolute decrease was greater in Caucasians (115.8 +/- 25.9 ml/min Versus 46.8 +/- 10.6 ml/min, respectively, p < .03). The diminished production of morphine after quinidi ne was associated in the Caucasians, but not in the Chinese, with a marked reduction in codeine's effects (p < .01). In conclusion, Chinese produce le ss morphine from codeine, exhibit reduced sensitivity to that morphine, and therefore might experience reduced analgesic effect in response to codeine . In addition, quinidine induced inhibition of codeine O-demethylation is e thnically dependent with the reduction being greater in Caucasians.