The molecular basis of CYP2D6-mediated N-dealkylation: balance between metabolic clearance routes and enzyme inhibition

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Britta BonnIsmael Zamora

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.

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Citations

Jul 30, 2011·Journal of Medicinal Chemistry·Samuel L C MoorsArnout Ceulemans
Dec 23, 2015·Rapid Communications in Mass Spectrometry : RCM·Esra Nurten Cece-EsencanIsmael Zamora
Sep 17, 2016·Angewandte Chemie·Brice SautierLars Wortmann
Mar 2, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Yuantao HuoShelli R McAlpine
Jun 20, 2020·Expert Review of Endocrinology & Metabolism·Naoto HamanoMasafumi Fukagawa
Jul 17, 2019·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Shin TokunagaTakehisa Kawata
Sep 3, 2020·Chemistry : a European Journal·Laura K BucktonShelli R McAlpine
May 27, 2021·Journal of Chemical Information and Modeling·Siyang TianDavid S Wishart
Jan 9, 2010·Journal of Chemical Information and Modeling·R F FreitasC A Montanari

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