RT Journal Article SR Electronic T1 The Molecular Basis of CYP2D6-Mediated N-Dealkylation: Balance between Metabolic Clearance Routes and Enzyme Inhibition JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 2199 OP 2210 DO 10.1124/dmd.108.022376 VO 36 IS 11 A1 Britta Bonn A1 Collen M. Masimirembwa A1 Yasmin Aristei A1 Ismael Zamora YR 2008 UL http://dmd.aspetjournals.org/content/36/11/2199.abstract AB 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. The American Society for Pharmacology and Experimental Therapeutics