Preliminary <i>in vitro</i> approach to evaluate the drug-drug interaction potential of EST73502, a dual µ-opioid receptor partial agonist and σ1 receptor antagonist
Creators: name: Ayet, Eva
name: Yeste, Sandra
name: Reinoso, Raquel F.
name: Pretel, María José
name: Balada, Ariadna
name: Serafini, Maria Teresa
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biophysics
subject: Biochemistry
subject: Space Science
subject: Cell Biology
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Ecology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: Cancer
subject: Hematology

description: The potential for drug-drug interactions (DDI) of EST73502 was preliminary explored <i>in vitro</i>. EST73502 is a new chemical entity intended for oral pain treatment with dual sigma-1 receptor (σ<sub>1</sub>R) antagonism and μ-opioid receptor (MOR) partial agonism, that presents a promising potent analgesic activity.Several enzymes were involved in EST73502 metabolism catalysing the formation of different metabolites, CYP3A4 and CYP2D6 being the main ones.Fraction unbound was determined due to its impact in interactions, a considerable proportion of EST73502 being available.EST73502 showed a low potential for CYP inhibition, except for CYP2D6 that showed time-dependent inhibition.No induction potential was found for CYP1A2 and 3A4, while CYP2B6 was induced at high concentration.EST73502 seemed to be a potential efflux transporter substrate (efflux ratio ≥ 2) but a negligible <i>in vivo</i> impact would be expected due to its high solubility and permeability in Caco-2 cells. P-gp inhibition was observed while no BCRP inhibition was detected.Preliminary <i>in vitro</i> interaction studies suggested that neither CYPs nor efflux transporters interactions would preclude further development of EST73502 to thoroughly assess the clinical relevance of these findings. The potential for drug-drug interactions (DDI) of EST73502 was preliminary explored <i>in vitro</i>. EST73502 is a new chemical entity intended for oral pain treatment with dual sigma-1 receptor (σ<sub>1</sub>R) antagonism and μ-opioid receptor (MOR) partial agonism, that presents a promising potent analgesic activity. Several enzymes were involved in EST73502 metabolism catalysing the formation of different metabolites, CYP3A4 and CYP2D6 being the main ones. Fraction unbound was determined due to its impact in interactions, a considerable proportion of EST73502 being available. EST73502 showed a low potential for CYP inhibition, except for CYP2D6 that showed time-dependent inhibition. No induction potential was found for CYP1A2 and 3A4, while CYP2B6 was induced at high concentration. EST73502 seemed to be a potential efflux transporter substrate (efflux ratio ≥ 2) but a negligible <i>in vivo</i> impact would be expected due to its high solubility and permeability in Caco-2 cells. P-gp inhibition was observed while no BCRP inhibition was detected. Preliminary <i>in vitro</i> interaction studies suggested that neither CYPs nor efflux transporters interactions would preclude further development of EST73502 to thoroughly assess the clinical relevance of these findings.