DIFFERENT EFFECTS OF INHIBITORS ON THE O-DEMETHYLATION AND N-DEMETHYLATION OF CODEINE IN HUMAN LIVER-MICROSOMES

Objective: The O- and N-demethylation of codeine is catalysed by CYP2D 6 and CYP3A4 respectively. The formation rates of morphine by O-demeth ylation and norcodeine by N-demethylation were studied in two sets of human liver microsomes. Results: Relatively high K-m values were found for both O- and N-demethylations, suggesting a low affinity to the co rresponding enzymes. The inhibitory effects of various drugs were foun d to be different for O- and N-demethylations. The substrates of CYP2D 6 such as thioridazine, amitriptyline and metoprolol inhibited the O-d emethylation of codeine preferentially, while the substrates of CYP3A4 such as cyclosporine A, midazolam and erythromycin were all strong in hibitors of the N-demethylation of codeine. Quinidine and lignocaine, although they are substrates of CYP3A, showed preferential inhibition over the O-demethylation of codeine, suggesting a low affinity to the CYP3A. Methadone and dextropropoxyphene showed a preferential inhibiti on of CYP2D6 over CYP3A, while theophylline did not inhibit the O- or N-demethylation to a greater extent. Conclusion: It seems that there w as a good correspondence between the capacity of drugs to inhibit the O- and N-demethylation of codeine in human liver microsomes and their apparent metabolism by CYP2D6 or CYP3A4, respectively in vivo in man, suggesting that this in vitro inhibition test may be a useful screen f or drugs which interact with these two important drug-metabolising enz ymes.