title: Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine.
abstract: OBJECTIVE
  Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated.
  
  
  METHODS
  The kinetics of formation of N- and O-demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied.
  
  
  RESULTS
  Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N-demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N-demethylation in both extensive and poor metabolizers. The CYP3A inducer, alpha-naphthoflavone, increased N-demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar Km values. The kinetic constants for O-demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O-demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer.
  
  
  CONCLUSIONS
  CYP2D6 is the major enzyme mediating O-demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A.
authors.affiliation: Centre for Pharmaceutical Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide.
authors.forename: L C
authors.initials: LC
authors.lastname: Kirkwood
authors.forename: R L
authors.initials: RL
authors.lastname: Nation
authors.forename: A A
authors.initials: AA
authors.lastname: Somogyi
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D019138:Antibodies, Blocking / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D003061:Codeine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D003640:Dealkylation; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D019138:Antibodies, Blocking; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; C014481:dihydrocodeine; D003061:Codeine