title: Different effects of inhibitors on the O- and N-demethylation of codeine in human liver microsomes.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology, Huddinge University Hospital, Sweden.
authors.forename: Q Y
authors.initials: QY
authors.lastname: Yue
authors.forename: J
authors.initials: J
authors.lastname: Säwe
mesh_terms: D003061:Codeine / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D003061:Codeine