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
Romain Pelletier,
Thomas Gicquel,
Mélanie Simoes Eugenio,
Pierre-Jean Ferron,
Isabelle Morel,
Claire Delehouzé,
Marie-Thérèse Dimanche-Boitrel,
Morgane Rousselot,
Brendan Le Daré
Affiliations
Romain Pelletier
Institut NuMeCan (Nutrition, Metabolism and Cancer), INSERM, INRAE, CHU Rennes, PREVITOX Network, 35033 Rennes, France
Thomas Gicquel
Institut NuMeCan (Nutrition, Metabolism and Cancer), INSERM, INRAE, CHU Rennes, PREVITOX Network, 35033 Rennes, France
Mélanie Simoes Eugenio
IRSET (Institut de Recherche en Santé, Environnement et Travail)—UMR_S 1085, Univ Rennes, Inserm, EHESP, 35000 Rennes, France
Pierre-Jean Ferron
Institut NuMeCan (Nutrition, Metabolism and Cancer), INSERM, INRAE, CHU Rennes, PREVITOX Network, 35033 Rennes, France
Isabelle Morel
Institut NuMeCan (Nutrition, Metabolism and Cancer), INSERM, INRAE, CHU Rennes, PREVITOX Network, 35033 Rennes, France
Claire Delehouzé
SeaBeLife SAS, Station Biologique, Place Georges Teissier, 29680 Roscoff, France
Marie-Thérèse Dimanche-Boitrel
IRSET (Institut de Recherche en Santé, Environnement et Travail)—UMR_S 1085, Univ Rennes, Inserm, EHESP, 35000 Rennes, France
Morgane Rousselot
SeaBeLife SAS, Station Biologique, Place Georges Teissier, 29680 Roscoff, France
Brendan Le Daré
Institut NuMeCan (Nutrition, Metabolism and Cancer), INSERM, INRAE, CHU Rennes, PREVITOX Network, 35033 Rennes, France
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.
