Carbamazepine and cigarette smoking induce differentially the metabolism of codeine in man

The inducibility of codeine metabolism by carbamazepine (CBZ) and cigarette smoking has been investigated. A single oral dose of 25 mg of codeine was given to seven epileptic patients before and after 3 weeks' regular CBZ treatment (400-600 mg per day). Codeine was also given to nine volunteers who were heavy smokers (20 cigarettes per day) and to nine non-smokers as controls. All subjects were found to be extensive metabolizers of codeine by O-demethylation. Urine was collected over 8 h following codeine intake. Codeine and the metabolites were analysed with HPLC. CBZ significantly increased the urinary excretion of the N-demethylated metabolite, norcodeine (NC) which led to a significant decrease in the metabolic ratio (MR) for N-demethylation. The O-demethylation was not significantly altered. The excretion of normorphine, an active metabolite formed through both O- and N-demethylation of codeine increased by almost three-fold after CBZ treatment. Contrary to CBZ treatment, cigarette smoking slightly but significantly induced the glucuronidation of codeine as shown by a decreased MR for glucuronidation in the smokers, while the O- and N-demethylations were not significantly changed as indicated by the similar MRs in smokers and in non-smokers. These results suggest that CBZ and cigarette smoking selectively induce different metabolizing enzymes. The polymorphic O-demethylation is relatively stable to these factors.