Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase catalyzing debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufI).

Codeine O-demethylation to its active moiety morphine was investigated in human liver microsomes from 1 poor and 5 extensive metabolizer subjects (debrisoquine-type of oxidation polymorphism). Apparent Km of the reaction in one extensive metabolizer's microsomes was 149 microM and Vmax 17.6 nmol X mg P-1 X hour-1 versus greater than 1 mM and 1.6 nmol X mg P-1 X hour-1 respectively in one poor metabolizer. In vitro morphine production was competitively inhibited by quinidine (Ki 15 nM), the selective inhibitor of cytochrome P-450 dbl/bufI. There was also an excellent correlation between dextromethorphan O-demethylation, a prototype reaction for cytochrome P-450 dbl/bufI activity, and codeine O-demethylation. These data allow to conclude that codeine bioactivation to morphine is dependent on the polymorphic monooxygenase known as cytochrome db1/bufI.