ARIADNE – ADME platform

ADME and Pharmacocinétique (PK)

plateforme ariadne adme

Presentation

Evaluation of ADME parameters early in the discovery process is widely used during target validation, hit-discovery, hit-to-lead optimisation stages. ARIADNE-ADME platform allows to evaluate these parameters rapidly.

PK in rodents. We have decided to help further medicinal chemists in their optimisation efforts and to provide as early as possible project leaders with the relevant information to select the best compounds for in vivo experiments and to interpret in vivo data collected on the model. In our organisation, only compounds with relevant pharmacokinetic (Cmax and clearance) will be administered to animal model. This is the only way to understand the phenotypic and biological observations made on the animal. It will also save animal lives, since only compounds that could realistically reach the target compartment and last long enough there will be administered. Last but not least, together with in vitro PK data (plasma and microsomal stability, solubility…) these early in vivo data will drive the optimisation of the lead structure toward the best possible in vivo performance.

The Ariadne-ADME platform is part of the National Research Infrastructure ChemBioFrance.

Know-how and services offered : Our ADME/PK and bioanalysis experts offer a custom-based service and experience. Sample preparation and bioanalysis are performed by an engineer using our LC-MS/MS platform.

Physical chemistry properties : kinetic solubility, thermodynamic solubility, lipophilicity (LogD), chemical stability.

Metabolic stability : microsomes, plasma, esterases function exploration.

Distribution : Caco-2 permeation studies, Plasma Protein-Binding.

Safety : GSH-adduct detection.

In vivo PK parameters : time to maximum plasma concentration, area under the plasma drug concentration–time curve, volume of distribution, clearance, terminal elimination half-life, bioavailability, concentration in organs.

Bioanalysis is performed using LC-MS/MS: UPLC Acquity I Class (Waters) coupled to a triple quadrupole Xevo TQD (Waters) equipped with ESI source. 

In silico tools : Software tools are developed to calculate parameters in silico and predict bioavailability (Pipeline PilotTM or Chem AxonTM).

Highlights

  • ARIADNE-ADME technicians, engineers and researchers are committed to finding a treatment for the COVID-19 pandemic. A molecule active in vitro on SARS-CoV-2 infection was discovered by cell screening of a library of 2000 drugs on the ARIADNE-screening platform. This discovery is the result of collaboration with Drs Sandrine Belouzard and Jean Dubuisson from the Center for Infection and Immunity of Lille and researchers from the company Apteeus. Before initiating the clinical phase in humans, several studies were carried out in vivo. All the samples from these animal studies – plasma and tissues (lungs, liver) – were analyzed on the ARIADNE-ADME platform. In parallel, several in vitro studies were also carried out on various hepatic fractions from different species in order to study and understand the metabolism of the active molecule.

Members

Benoit DEPREZ
PU, Univ Lille

Florence LEORUX
IR, Inserm

Catherine PIVETEAU
IE, Univ Lille

Alexandre BIELA
Tech, IPL

Valentin GUILLAUME
CE, IPL

Julie DUMONT
AI, Univ Lille

Adrien HADRELAN
IE, Inserm

Publications

Hoguet, V. et al.
Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure-Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor.
J Med Chem (2021) doi:10.1021/acs.jmedchem.0c01774.

Villemagne, B. et al.
Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity.
ACS Infect Dis 6, 366–378 (2020).

Montaigne, D. et al.
Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study.
Lancet 391, 59–69 (2018).

Hermant, P. et al.
Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox.
J Med Chem 60, 9067–9089 (2017).

Team contact

Florence Leroux
Head of the plateform

florence.leroux@pasteur-lille.fr