A Transversal Approach Combining In Silico, In Vitro and In Vivo Models to Describe the Metabolism of the Receptor Interacting Protein 1 Kinase Inhibitor Sibiriline

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2022 Dec 23

PMID 36559159

Authors

Romain Pelletier

Thomas Gicquel

Melanie Simoes Eugenio

Pierre-Jean Ferron

Isabelle Morel

Claire Delehouze

Marie-Therese Dimanche-Boitrel

Morgane Rousselot

Brendan Le Dare

Affiliations

Soon will be listed here.

Abstract

Sibiriline is a novel drug inhibiting receptor-interacting protein 1 kinase (RIPK1) and necroptosis, a regulated form of cell death involved in several disease models. In this study, we aimed to investigate the metabolic fate of sibiriline in a cross-sectional manner using an in silico prediction, coupled with in vitro and in vivo experiments. In silico predictions were performed using GLORYx and Biotransformer 3.0 freeware; in vitro incubation was performed on differentiated human HepaRG cells, and in vivo experiments including a pharmacokinetic study were performed on mice treated with sibiriline. HepaRG culture supernatants and mice plasma samples were analyzed with ultra-high-performance liquid chromatography, coupled with tandem mass spectrometry (LC-HRMS/MS). The molecular networking bioinformatics tool applied to LC-HRMS/MS data allowed us to visualize the sibiriline metabolism kinetics. Overall, 14 metabolites, mostly produced by Phase II transformations (glucuronidation and sulfation) were identified. These data provide initial reassurance regarding the toxicology of this new RIPK1 inhibitor, although further studies are required.

Citing Articles

In silico and in vitro metabolism studies of the new synthetic opiate AP-237 (bucinnazine) using bioinformatics tools.

Pelletier R, Bourdais A, Fabresse N, Ferron P, Morel I, Gicquel T Arch Toxicol. 2023; 98(1):165-179.

PMID: 37839054 DOI: 10.1007/s00204-023-03617-x.

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