Preliminary in vitro approach to evaluate the drug-drug interaction potential of EST73502, a dual µ-opioid receptor partial agonist and σ1 receptor antagonist

Abstract

1. The potential for drug-drug interactions (DDI) of EST73502 was preliminary explored in vitro. EST73502 is a new chemical entity intended for oral pain treatment with dual sigma-1 receptor (σ₁R) antagonism and μ-opioid receptor (MOR) partial agonism, that presents a promising potent analgesic activity.

2. Several enzymes were involved in EST73502 metabolism catalysing the formation of different metabolites, CYP3A4 and CYP2D6 being the main ones.

3. Fraction unbound was determined due to its impact in interactions, a considerable proportion of EST73502 being available.

4. EST73502 showed a low potential for CYP inhibition, except for CYP2D6 that showed time-dependent inhibition.

5. No induction potential was found for CYP1A2 and 3A4, while CYP2B6 was induced at high concentration.

6. EST73502 seemed to be a potential efflux transporter substrate (efflux ratio ≥ 2) but a negligible in vivo 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.

7. Preliminary in vitro 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.

Keywords:

• Phenotyping
• Fraction unbound
• CYP inhibition
• CYP induction
• P-gp interaction
• BCRP interaction

Acknowledgements

We thank our colleagues at Drug Discovery & Preclinical Development at ESTEVE Pharmaceuticals R&D for their contribution and support.

Disclosure statement

The authors are past full-time employees of ESTEVE Pharmaceuticals and report no conflict of interest.

Additional information

Funding

This work was a part of activities in R&D projects IDI20130943 and IDI20150915 supported by the Spanish "Ministerio de Economía y Competitividad" (MINECO), through the "Centro para el Desarrollo Tecnológico Industrial" (CDTI), co-financed by the European Union trough the European Regional Development Fund (ERDF; "Fondo Europeo de Desarrollo Regional", FEDER).