Endogenous codeine and morphine in poor and extensive metabolisers of the CYP2D6 (debrisoquine/sparteine) polymorphism.

Codeine and morphine are endogenous substances. Following administration of exogenous codeine the biotransformation to morphine is catalyzed by CYP2D6, which exhibits a genetic so-called debrisoquine/sparteine polymorphism which is expressed in two phenotypes, the extensive and poor metaboliser phenotypes. Poor metabolisers form only trace amounts of morphine. If endogenous morphine is biosynthesised in humans via similar routes as in the poppy plant, two of the steps involved are mediated by CYP2D6, namely thebaine O-demethylation to oripavine and codeine O-demethylation to morphine. Poor metabolisers should therefore have a much lower endogenous morphine formation than extensive metabolisers. The urinary excretion of endogenous codeine and morphine were investigated in 20 extensive and 20 poor metabolisers of CYP2D6. Substantial interindividual variation in codeine (7-6851 pmol/24 hr) and morphine (32-35471 pmol/24 hr) excretion was observed. However, there were no phenotype-related differences in endogenous codeine and morphine excretion. Administration of the competitive CYP2D6 inhibitor quinidine had no significant effect on endogenous codeine and morphine excretion in extensive metabolisers. In conclusion, in contrast to exogenous codeine O-demethylation to morphine CYP2D6 appears not to be involved in the biosynthesis of morphine in humans.