ADME and Pharmacokinetics (PK)
ARIADNE comprises two platforms, ARIADNE-Screening and ARIADNE-ADME, working independently but in a complementary fashion. Their objective is to discover small chemical molecules useful in therapeutics or for exploring living organisms, and to characterize their ADME properties. ARIADNE-Screening brings together a range of expertise and equipment dedicated to screening biological disruptors such as small chemical molecules or siRNA libraries. ARIADNE-ADME, for its part, quantifies the parameters that characterize the ability of molecules to be absorbed, distributed, metabolized, and eliminated in vivo (ADME). In medicinal chemistry research projects, the evaluation of ADME parameters is widely used during the target validation, hit discovery, and hit-to-lead phases.
Pharmacokinetics in rodents. We propose to provide researchers with the information needed to select the best compounds for in vivo proof-of-concept experiments. We believe that only compounds with relevant pharmacokinetics should be administered to the animal pharmacological model. Indeed, only the use of compounds capable of realistically reaching the target compartment and remaining there for a sufficient duration guarantees that it will be possible to subsequently understand the phenotypic and biological observations made in the animal. Thus, combined with in vitro ADME data (plasma and microsomal stability, solubility, etc.), this initial in vivo data will guide the optimization of the compound structure to achieve the best possible in vivo performance.
Expertise and services offered: Our ADME/PK and bioanalysis experts offer a personalized service. Sample preparation and bioanalysis are performed on the LC-MS/MS systems of Unit U1177.
Physicochemical properties: Kinetic solubility, thermodynamic solubility, lipophilicity (LogD), chemical stability.
Metabolic stability: microsomes, plasma, exploration of the role of esterases.
Distribution: Permeability on Caco-2, binding to plasma proteins.
Security: detection of GSH adducts.
In vivo pharmacokinetic parameters: time to maximum plasma concentration, exposure (area under the plasma concentration-time curve), volume of distribution, clearance, terminal elimination half-life, bioavailability, organ concentration.
La bioanalysis is carried out on an Acquity I-Class UPLC chain (Waters) coupled to a Xevo TQD triple quadrupole (Waters), equipped with an ESI source.
In silico: Tools are being developed to calculate in silico parameters and predict bioavailability (Pipeline PilotTM or Chem AxonTM).
News
The technicians, engineers, and researchers at ARIADNE-ADME have been engaged in the search for a treatment against the COVID-19 pandemic. An active molecule against SARS-CoV-2 infection was discovered through cell screening of a library of 2000 drugs on the ARIADNE-Screening platform. This discovery is the result of a collaboration with Dr. Sandrine Belouzard and Dr. Jean Dubuisson of the Lille Center for Infection and Immunity and researchers from the company Apteeus. Before initiating the clinical phase in humans, several in vivo studies were conducted. All samples from these studies—plasma and tissues (lungs, liver)—were analyzed on the ARIADNE-ADME platform. In parallel, several in vitro studies were also conducted on different liver fractions from various species to study and understand the metabolism of the active molecule.
Members
DEPREZ Benoît
Director UMR1177 Inserm - Professor PhD, Pharm University of Lille
N. ORCID: 0000-0002-2777-4538
Adrien HADRELAN
IE, Inserm
Team contact
Publications
J Med Chem (2021) doi:10.1021/acs.jmedchem.0c01774.
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.
ACS Infect Dis 6, 366–378 (2020).
Fragment-Based Optimized EthR Inhibitors with in Vivo Ethionamide Boosting Activity.
Lancet 391, 59–69 (2018).
Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-center propensity-matched cohort study and a randomized study.
J Med Chem 60, 9067–9089 (2017).
