ADME of Therapeutics

ADME of Therapeutics

ADME of Therapeutics (ADMEoT) is the SciLifeLab DDD platform unit for absorption, distribution, metabolism, excretion (ADME), and preclinical profiling.

ADMEoT uses a state of the art laboratory and cutting edge research to help Swedish academic projects in the optimization of hit compound series and deliver lead compounds and candidate drugs of the highest possible quality. We add scientific value to all stages of the preclinical drug discovery and development process.

The ADMEoT unit in collaboration with the Laboratory of Daniel Globisch (Department of Chemistry, Uppsala University, with support from the SciLifeLab SFO Committee at Uppsala University, has started a dedicated Metabolomics Capability for Drug Discovery. The primary objective of the Metabolomics Capability is to investigate drug-induced changes of the metabolome and, together with other metabolomics units within SciLifeLab, to strengthen Sweden’s drug discovery environment and maximize the chances of success for ongoing and future Swedish drug discovery projects.

ADMEoT, as a part of UDOPP (a local platform at the Department of Pharmacy, Uppsala University), is also affiliated with the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), MURYXIN project.

SERVICES

Determination and prediction of physico-chemical properties:

• LogP, LogD and pKa determination
• Chemical stability
• Solubility (kinetic and thermodynamic) and its pH dependence

ADME (Absorption, Distribution, Metabolism, Excretion):

• In silico models for prediction of ADME properties
• Plasma protein binding and stability (human and animal plasma)
• Cell-membrane permeability in Caco-2 and MDCK cells
• Active cellular uptake and efflux using cell based assays (identification and characterization)
• Inhibition of active transport (transporter related drug-drug interactions, DDI)
• Metabolic stability in liver microsomes (human an animal)
• Metabolic stability in hepatocytes (human and animal)
• Biotransformation – metabolite profiling and identification
• Metabolic enzyme identification studies (reaction phenotyping)
• Cytochrome P450 inhibition and induction (metabolism related DDI)

Liquid Chromatography-Mass spectrometry (LC-MS):

• Analysis of in vitro ADME samples
• Bioanalysis of animal and human in vivo samples
• Proteomics (targeted and global)

Biopharmaceutics:

• Intact mass determination
• Peptide mapping
• Bioanalysis: mass spectrometry and ligand based assays (LBA)
• Anti-drug antibodies (ADA) characterization: LBA assay
• Protein characterization

Design and evaluation of pharmacokinetic (PK) studies

Physiological-based pharmacokinetics (PBPK) simulations

PK/PD modelling

Metabolomics Capability (Unit) for Drug Discovery (in collaboration with Prof Daniel Globisch laboratory)

• Prototype Drug Profiling (biochemical fingerprints) & Target Engagement
  • Quantifies endogenous metabolites
  • Provides biochemical fingerprints
  • Confirms target engagement
• Mechanism of Action studies
  • Reveals how prototype drugs affect endogenous metabolism
  • Clarifies drug action pathways
• Metabolomics in combination with protein analysis (proteomics)
• Enhanced Biomarker Discovery
• Support to Phenotypic Drug Discovery
• Advancements in Personalized Medicine

APPLICATIONS

• Physico-chemical and ADME optimization of the hit and lead compound libraries
• Preclinical characterization of drug candidates
• Drug discovery and development

EQUIPMENT

• BSL2 cell culture laboratory with attached equipment
• 2 x UPLC-MS/MS TQ-S micro from Waters
• 2D LC- IM-QToF SYNAPT G2-Si from Waters
• 2D LC- IM-QToF SYNAPT XS from Waters
• nanoLC/UPLC-Q Exactive HF OrbiTrap from Thermo
• UPLC-UV/QDa from Waters

DETAILED INFORMATION