Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes.
Article Details
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Yue QY, Sawe J
Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes.
Eur J Clin Pharmacol. 1997;52(1):41-7.
- PubMed ID
- 9143866 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Amitriptyline Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Codeine Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Codeine Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails Dextropropoxyphene Cytochrome P450 2D6 Protein Humans UnknownSubstrateInhibitorDetails Dextropropoxyphene Cytochrome P450 3A Subfamily (Protein Group) Protein group Humans UnknownInhibitorDetails Methadone Cytochrome P450 2D6 Protein Humans NoSubstrateInhibitorDetails Methadone Cytochrome P450 3A Subfamily (Protein Group) Protein group Humans NoInhibitorDetails