QUANTIFICATION OF THE O-DEMETHYLATED AND N-DEMETHYLATED AND THE GLUCURONIDATED METABOLITES OF CODEINE RELATIVE TO THE DEBRISOQUINE METABOLIC RATIO IN URINE IN ULTRARAPID, RAPID, AND POOR DEBRISOQUINE HYDROXYLATORS

The O-demethylation of codeine is polymorphic and catalyzed by CYP2D6. The metabolites of codeine formed through O- and N-demethylation as w ell as glucuronidation were quantified in the ultrarapid metabolizers of debrisoquine and compared with the normal extensive (EM) and poor m etabolizers (PM). The urinary codeine and its seven metabolites were d etected after 25 mg codeine in 24 healthy Caucasian subjects with low debrisoquine metabolic ratios (MR, less than or equal to 0.11) and a g roup of 132 subjects tested earlier with codeine and debrisoquine incl uding 114 EMs (MR < 12.6) and 18 PMs (MR > 12.6). Whereas the O-demeth ylated metabolites accounted for <0.4% of the total recovery on averag e in the PMs and 1.7% to 8.7% in the EMs, they accounted for 15.3% in the 24 subjects with ultrarapid metabolism of debrisoquine. This study suggests that the ultrarapid debrisoquine hydroxylators may develop i ncreased O-demethylated metabolite-dependent effects or side-effects o f codeine.