Eur J Clin Pharmacol. 1997;52(1):41-7.  

Different effects of inhibitors on the O- and N-demethylation of codeine in
human liver microsomes.

Yue QY, Sawe J.

Department of Clinical Pharmacology, Huddinge University Hospital, Sweden.

OBJECTIVE: The O- and N-demethylation of codeine is catalysed by CYP2D6 and
CYP3A4 respectively. The formation rates of morphine by O-demethylation 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 corresponding enzymes. The
inhibitory effects of various drugs were found to be different for O- and
N-demethylations. The substrates of CYP2D6 such as thioridazine, amitriptyline
and metoprolol inhibited the O-demethylation of codeine preferentially, while
the substrates of CYP3A4 such as cyclosporine A, midazolam and erythromycin were
all strong inhibitors 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 inhibition of
CYP2D6 over CYP3A, while theophylline did not inhibit the O- or N-demethylation
to a greater extent. CONCLUSION: It seems that there was 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 for drugs which interact with these two important
drug-metabolising enzymes.

PMID: 9143866 [PubMed - indexed for MEDLINE]