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 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.
Footnotes
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doi:10.1124/dmd.108.022376.
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ABBREVIATIONS: P450, cytochrome P450; Clint, intrinsic clearance; SOM, site of metabolism; DXM, dextromethorphan; DXO, dextrorphan; MEM, 3-methoxymorphinan; AMMC, 4-aminomethyl-7-methoxycoumarine; GRID-MIFs, GRID-derived molecular interaction fields; FLAP, Fingerprints for Proteins and Ligands; HPLC, high-performance liquid chromatography; ESI, electrospray ionization; LC-MS, liquid chromatography-mass spectrometry; MRM, multiple reaction monitoring.
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↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
- Received May 15, 2008.
- Accepted August 22, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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