New insights into quetiapine metabolism using molecular networking

Brendan Le Daré,Pierre-Jean Ferron,Isabelle Morel,Bruno Clément,Pierre-Marie Allard,Thomas Gicquel

doi:10.1038/s41598-020-77106-x

Abstract

Metabolism is involved in both pharmacology and toxicology of most xenobiotics including drugs. Yet, visualization tools facilitating metabolism exploration are still underused, despite the availibility of pertinent bioinformatics solutions. Since molecular networking appears as a suitable tool to explore structurally related molecules, we aimed to investigate its interest in in vitro metabolism exploration. Quetiapine, a widely prescribed antipsychotic drug, undergoes well-described extensive metabolism, and is therefore an ideal candidate for such a proof of concept. Quetiapine was incubated in metabolically competent human liver cell models (HepaRG) for different times (0 h, 3 h, 8 h, 24 h) with or without cytochrom P450 (CYP) inhibitor (ketoconazole as CYP3A4/5 inhibitor and quinidine as CYP2D6 inhibitor), in order to study its metabolism kinetic and pathways. HepaRG culture supernatants were analyzed on an ultra-high performance liquid chromatography coupled with tandem mass spectrometry (LC-HRMS/MS). Molecular networking approach on LC-HRMS/MS data allowed to quickly visualize the quetiapine metabolism kinetics and determine the major metabolic pathways (CYP3A4/5 and/or CYP2D6) involved in metabolite formation. In addition, two unknown putative metabolites have been detected. In vitro metabolite findings were confirmed in blood sample from a patient treated with quetiapine. This is the first report using LC-HRMS/MS untargeted screening and molecular networking to explore in vitro drug metabolism. Our data provide new evidences of the interest of molecular networking in drug metabolism exploration and allow our in vitro model consistency assessment.

Highlights

Metabolism is involved in both pharmacology and toxicology of most xenobiotics including drugs
Molecular networking (MN) has already proven its interest in plant species profiling10, metabolomics[11], the dereplication of naturally produced s ubstances[12], and in drug metabolism analysis for in vivo
HepaRG cells have been successfully used in m etabolomics[22] and have shown greater metabolite production compared to human liver microsome due to the lack of sulfation, methylation, acetylation or glutathione conjugation in this latter m odel[23]

Summary

Introduction

Metabolism is involved in both pharmacology and toxicology of most xenobiotics including drugs. Molecular networking approach on LC-HRMS/ MS data allowed to quickly visualize the quetiapine metabolism kinetics and determine the major metabolic pathways (CYP3A4/5 and/or CYP2D6) involved in metabolite formation. In vitro metabolite findings were confirmed in blood sample from a patient treated with quetiapine This is the first report using LC-HRMS/MS untargeted screening and molecular networking to explore in vitro drug metabolism. Our data provide new evidences of the interest of molecular networking in drug metabolism exploration and allow our in vitro model consistency assessment. Quetiapine is an orally administered atypical antipsychotic indicated in schizophrenia treatment, bipolar disorders and as an adjuvant treatment in major depressive disorders[1] Prescribed in these indications, this dibenzodiazepine derivative shows affinity for various neurotransmitter receptors including serotonin, dopamine, histamine and adrenergic receptors and has binding characteristics at the dopamine-2 receptor similar to those of clozapine[2]. There is a large body of evidence that differentiated HepaRG culture is a relevant cell model system for drug metabolism study

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