ENDOGENOUS CODEINE AND MORPHINE IN POOR AND EXTENSIVE METABOLIZERS OFTHE CYP2D6 (DEBRISOQUINE SPARTEINE) POLYMORPHISM/

Codeine and morphine are endogenous substances. Following administrati on 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 p oor metaboliser phenotypes. Poor metabolisers form only trace amounts of morphine. If endogenous morphine is biosynthesised in humans via si milar routes as in the poppy plant, two of the steps involved are medi ated by CYP2D6, namely thebaine O-demethylation to oripavine and codei ne O-demethylation to morphine. Poor metabolisers should therefore hav e a much lower endogenous morphine formation than extensive metabolise rs. The urinary excretion of endogenous codeine and morphine were inve stigated in 20 extensive and 20 poor metabolisers of CYP2D6. Substanti al interindividual variation in codeine (7-6851 pmol/24 hr) and morphi ne(32-35471 pmol/24 hr) excretion was observed. However, there were no phenotype-related differences in endogenous codeine and morphine excr etion. Administration of the competitive CYP2D6 inhibitor quinidine ha d no significant effect on endogenous codeine and morphine excretion i n extensive metabolisers. In conclusion, in contrast to exogenous code ine O-demethylation to morphine CYP2D6 appears not to be involved in t he biosynthesis of morphine in humans.