The molecular basis of CYP2D6-mediated N-dealkylation: balance between metabolic clearance routes and enzyme inhibition.
N-dealkylation is a commonly observed metabolic reaction for drugs containing secondary and tertiary amines. On searching the literature, it is obvious that this reaction is far less common among cytochrome P450 2D6 catalyzed reactions compared with other cytochromes P450. The CYP2D6 pharmacophore and characteristic features in the active site cavity suggest a favored substrate orientation that prevents N-dealkylation from occurring. In this study, the literature was searched for N-dealkylated and non-N-dealkylated CYP2D6 substrates. The hypothesis that was suggested and confirmed demonstrated that N-dealkylation occurs by this enzyme when the preferred site of metabolism is blocked toward other oxidative metabolic pathways. An interesting observation was also that addition of stable groups at preferred sites of metabolism generally improved the metabolic stability but also resulted in retained or increased inhibition of the enzyme. In addition, the effect of pH on N- and O-dealkylation of dextromethorphan was shown to be consistent with the hypothesis that an ionized amino function favored substrate dockings resulting in O-dealkylation.
Bonn
Britta
B
Discovery DMPK & Bioanalytical Chemistry, AstraZeneca R&D Mölndal, SE-431 81 Mölndal, Sweden. kjelland@chem.gu.se
Masimirembwa
Collen M
CM
Aristei
Yasmin
Y
Zamora
Ismael
I
D020134:Catalytic Domain / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003640:Dealkylation / Q000502:physiology; D003915:Dextromethorphan / Q000032:analysis / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000032:analysis / Q000378:metabolism; D004795:Enzyme Stability / Q000502:physiology; D006801:Humans; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity / Q000235:genetics
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6