Received for publication May 15, 2008.
Revised August 6, 2008.
Accepted for publication August 22, 2008.

The Molecular Basis of CYP2D6 mediated N dealkylation - Balance between metabolic clearance routes and enzyme inhibition

Abstract

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 to other CYP's. 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 suggested and confirmed was that N dealkylation occurs by this enzyme when the preferred site of metabolism is blocked towards 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.

Key words: computer modeling and simulation, CYP2D, metabolite identification