Title:Predicted Contributions of Flavin-containing Monooxygenases to the N-oxygenation of Drug Candidates Based on their Estimated Base Dissociation Constants
VOLUME: 22 ISSUE: 3
Author(s):Tomomi Taniguchi-Takizawa*, Harutoshi Kato, Makiko Shimizu and Hiroshi Yamazaki*
Affiliation:Discovery Technology Laboratories, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Drug Metabolism and Pharmacokinetics Laboratories, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo
Keywords:FMO, N-oxide formation, pKa base, optimal pH, P450, drug development.
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.
