TY - JOUR

T1 - Multiwell photocatalytic microreactor device integrating drug biotransformation modeling and sample preparation on a MALDI target

AU - Gorbunov, Alexander

AU - Bardin, Alexander

AU - Ilyushonok, Semyon

AU - Kovach, Jacob

AU - Petrenko, Artem

AU - Sukhodolov, Nikolai

AU - Krasnov, Konstantin

AU - Krasnov, Nikolai

AU - Zorin, Ivan

AU - Obornev, Alexander

AU - Babakov, Vladimir

AU - Radilov, Andrey

AU - Podolskaya, Ekaterina

N1 - Publisher Copyright: © 2022 Elsevier B.V.

PY - 2022/7/1

Y1 - 2022/7/1

N2 - Metabolic conversion of drugs to chemically reactive products, known as bioactivation, is considered to underlie the adverse drug reactions such as idiosyncratic hepatotoxicity. As bioactivation of most drugs involves phase I oxidation, UV-induced TiO2 photocatalytic oxidation (UV/TiO2-PCO) can be used as a fast, simple and inexpensive non-enzymatic method of oxidative metabolism simulation allowing for rapid preliminary screening of candidate drugs for reactive metabolite formation. We developed and evaluated a novel prototype 96-well on-target UV/TiO2-photocatalytic microreactor setup (PCμR96) that integrates drug metabolism simulation and sample preparation directly on a MALDI target. PCμR96 allows to sequentially perform UV/TiO2-PCO of xenobiotics, GSH or protein adduct formation, protein digestion and sample concentration, followed by surface- or matrix-assisted laser desorption ionization (SALDI/MALDI) mass spectrometry (MS). Amodiaquine (AQ), a well-studied antimalarial drug that is known to undergo oxidative biotransformation, was selected as a model compound. Oxidation products of AQ and their protein adducts were obtained using PCμR96 and identified by SALDI and MALDI MS/MS analysis. The achieved AQ oxidation products were in good agreement with the known AQ metabolites produced in biological systems. Two of the products were proved to be reactive towards cysteyl thiols of human globin.

AB - Metabolic conversion of drugs to chemically reactive products, known as bioactivation, is considered to underlie the adverse drug reactions such as idiosyncratic hepatotoxicity. As bioactivation of most drugs involves phase I oxidation, UV-induced TiO2 photocatalytic oxidation (UV/TiO2-PCO) can be used as a fast, simple and inexpensive non-enzymatic method of oxidative metabolism simulation allowing for rapid preliminary screening of candidate drugs for reactive metabolite formation. We developed and evaluated a novel prototype 96-well on-target UV/TiO2-photocatalytic microreactor setup (PCμR96) that integrates drug metabolism simulation and sample preparation directly on a MALDI target. PCμR96 allows to sequentially perform UV/TiO2-PCO of xenobiotics, GSH or protein adduct formation, protein digestion and sample concentration, followed by surface- or matrix-assisted laser desorption ionization (SALDI/MALDI) mass spectrometry (MS). Amodiaquine (AQ), a well-studied antimalarial drug that is known to undergo oxidative biotransformation, was selected as a model compound. Oxidation products of AQ and their protein adducts were obtained using PCμR96 and identified by SALDI and MALDI MS/MS analysis. The achieved AQ oxidation products were in good agreement with the known AQ metabolites produced in biological systems. Two of the products were proved to be reactive towards cysteyl thiols of human globin.

KW - Drug bioactivation

KW - MALDI

KW - Photocatalysis

KW - Reactive metabolites

KW - SALDI

KW - Titanium dioxide

UR - http://www.scopus.com/inward/record.url?scp=85126010407&partnerID=8YFLogxK

UR - https://www.mendeley.com/catalogue/60df3bed-f240-3fab-8edc-191775d1a376/

U2 - 10.1016/j.microc.2022.107362

DO - 10.1016/j.microc.2022.107362

M3 - Article

AN - SCOPUS:85126010407

VL - 178

JO - Microchemical Journal

JF - Microchemical Journal

SN - 0026-265X

M1 - 107362

ER -