Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.
CYP2D6 is polymorphically distributed so that in poor metabolizers enzyme activity is missing. The goal of this study was to compare the pharmacokinetics and pharmacodynamics of codeine with and without quinidine between Caucasian and Chinese extensive metabolizers of debrisoquin. Nine Caucasians and eight Chinese subjects received in random, double blind fashion, on two occasions, codeine 120 mg. with placebo or with quinidine 100 mg. Pharmacodynamic effects were determined over 6 h. Codeine-apparent clearance and partial metabolic clearance by O-demethylation were significantly greater in the 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/min, p <.02, respectively). Codeine's respiratory effects (except on resting ventilation) were significantly greater in the Caucasian than in the Chinese subjects (p <.05), but no interethnic differences were noted in codeine's effect on the digit symbol substitution test and pupillary ratio. No morphine or morphine metabolites were detected in plasma when codeine was coadministered with quinidine. Codeine O-demethylation was significantly reduced 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 quinidine was associated in the Caucasians, but not in the Chinese, with a marked reduction in codeine's effects (p <.01). In conclusion, Chinese produce less 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 ethnically dependent with the reduction being greater in Caucasians.
Caraco
Y
Y
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Sheller
J
J
Wood
A J
AJ
D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D044466:Asian People; D001711:Biotransformation; D003061:Codeine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D003640:Dealkylation; D003647:Debrisoquin / Q000378:metabolism; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D009020:Morphine / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D011680:Pupil / Q000187:drug effects; D011802:Quinidine / Q000009:adverse effects / Q000494:pharmacology*; D015656:Respiratory Mechanics / Q000187:drug effects; D044465:White People
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D009020:Morphine; D011802:Quinidine; D003061:Codeine; D003647:Debrisoquin