Quantification of the O- 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 well as glucuronidation were quantified in the ultrarapid metabolizers of debrisoquine and compared with the normal extensive (EM) and poor metabolizers (PM). The urinary codeine and its seven metabolites were detected after 25 mg codeine in 24 healthy Caucasian subjects with low debrisoquine metabolic ratios (MR, < or = 0.11) and a group of 132 subjects tested earlier with codeine and debrisoquine including 114 EMs (MR < 12.6) and 18 PMs (MR > 12.6). Whereas the O-demethylated metabolites accounted for < 0.4% of the total recovery on average 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 increased O-demethylated metabolite-dependent effects or side-effects of codeine.
Yue
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QY
Department of Clinical Pharmacology, Huddinge University Hospital, Sweden.
Alm
C
C
Svensson
J O
JO
Säwe
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D003061:Codeine / Q000378:metabolism* / Q000652:urine; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism*
D010090:Oxidoreductases, O-Demethylating; D019389:Cytochrome P-450 CYP2D6; D010089:Oxidoreductases, N-Demethylating; D014453:Glucuronosyltransferase; D003061:Codeine