Predicted Contributions of Flavin-containing Monooxygenases to the N-oxygenation of Drug Candidates Based on their Estimated Base Dissociation Constants

Author(s): Tomomi Taniguchi-Takizawa*, Harutoshi Kato, Makiko Shimizu, Hiroshi Yamazaki*

Journal Name: Current Drug Metabolism

Volume 22 , Issue 3 , 2021


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Graphical Abstract:


Abstract:

Aims: Base dissociation constants of 30 model chemicals were investigated to constitute potential determinant factors predicting the contributions of flavin-containing monooxygenases (FMOs).

Background: The contributions of FMOs to the metabolic elimination of new drug candidates could be underestimated under certain experimental conditions during drug development.

Objective: A method for predicting metabolic sites and the contributions of FMOs to N-oxygenations is proposed using a molecular descriptor, the base dissociation constant (pKa base), which can be estimated in silico using commonly available chemoinformatic prediction systems.

Methods: Model drugs and their oxidative pathways were surveyed in the literature to investigate the roles of FMOs in their N-oxygenations. The acid and base dissociation constants of the nitrogen moieties of 30 model substrates were estimated using well-established chemoinformatic software.

Results: The base dissociation constants of 30 model chemicals were classified into two groups based on the reported optimal in vitro pH of 8.4 for FMO enzymes as a key determinant factor. Among 18 substrates (e.g., trimethylamine, benzydamine, and itopride) with pKa (base) values in the range of 8.4-9.8, all N-oxygenated metabolites were reported to be predominantly catalyzed by FMOs. Except for three cases (xanomeline; L-775,606; and tozasertib), the nine substrates with pKa (base) values in the range 2.7-7.9 were only moderately or minorly N-oxygenated by FMOs in addition to their major metabolic pathway of oxidation mediated by cytochrome P450s. N-Oxygenation of T-1032 (with a pKa of 4.8) is mediated predominantly by P450 3A5, but not by FMO1/3.

Conclusion: The predicted contributions of FMOs to the N-oxygenation of drug candidates can be simply estimated using classic base dissociation constants.

Keywords: FMO, N-oxide formation, pKa base, optimal pH, P450, drug development.

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Article Details

VOLUME: 22
ISSUE: 3
Year: 2021
Published on: 21 April, 2021
Page: [208 - 214]
Pages: 7
DOI: 10.2174/1389200221666201207195758
Price: $65

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