ADMET Services

At Peakdale Molecular our range of in vitro ADMET models delivers high quality, accurate and reproducible data. With efficient turnaround times, we help accelerate our customers’ drug discovery programmes. In addition to our core assays, we offer clients the option of customised assay design within a completely confidential service.

Complementing our in vitro service, we offer in silico ADMET screening to aid compound design.

Our team is focused on generating high quality data from rigorously developed and validated assays. We support our clients with results interpretation and direct communication with our assay experts.

We endeavour to become your trusted service partner by offering a combination of speed, accuracy and customisation to every project we undertake.

Our ADMET services can be contracted per test and also through the FTE business model. A copy of our ADMET price list can be found at the bottom of the page.

Our in vitro ADMET services include:

Physicochemical Properties

  • Solubility (kinetic or thermodynamic) – Poor aqueous solubility limits oral absorption causing poor oral bioavailability, we utilise the shake-flask method.
  • Lipophilicity – Influences drug activity, and is correlated with solubility, permeability, metabolism, toxicity, protein binding and distribution. We estimate Log D (octanol : buffer) using the shake-flask method at pH 7.4.
  • Chemical Stability – Unstable compounds may be clinically unsuitable if effective concentrations cannot be maintained. We offer testing at a range of pHs.

Absorption

Drug permeability rates influence tissue penetration.

  • Caco-2 and MDCK-MDR1 Permeability. Both assays have the option of bidirectional permeability with P-gp substrate identification.
  • PAMPA. High throughput artificial membrane permeability. Choice of intestine or BBB models, which differ according to the particular lipids used.

Distribution

Distribution is usually concerned with the reversible movement of drugs from one site to another. We use equilibrium dialysis assays with the following range of tissues:

  • Plasma Protein Binding
  • Whole Blood Binding
  • Blood to Plasma Ratio
  • Brain Tissue Binding
  • Microsomal Binding

Metabolism

  • Metabolic Stability (microsomes, hepatocytes, S9, plasma) strongly influences therapeutic efficacy and toxicity. Rapid metabolism reduces bioavailability resulting in lower exposure at the therapeutic target. We determine half-life from multiple time-points in human and animal species.
  • CYP Inhibition may occur during co-administration of two or more drugs that compete for metabolism by a single enzyme. In this type of drug-drug interaction, the excluded drug may increase to toxic concentrations that could potentially be fatal. We use drug substrates and generate 6-point IC50 curves.
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  • Time-Dependent Inhibition may be due to quasi-irreversible inhibition where metabolites form stable complexes with the CYP, or irreversible inhibition where metabolites covalently bind to CY, in either case CYP enzymes are rendered inactive. We test against the 5 major CYPs using drug substrates.
  • CYP Reaction Phenotyping evaluates the relative contribution of each isoform in the metabolism of test compounds, and therefore the potential for involvement in drug-drug interactions.

Toxicity

  • Cytotoxicity is measured using cultured HepG2 cells, using multiple concentrations in triplicate to determine IG50 (MTS end-point).
  • Mitochondrial Toxicity is measured by comparing HepG2 cells cultured in two separate media types (i) glucose-rich (cells survive using energy via glycolysis; mitochondria are not essential), and (ii) glucose-free (cells cannot survive without energy from mitochondrial ATP). Hence, cell death in glucose-free but not in glucose-rich media reveals mitochondrial toxicity.

Bioassays

We determine the potency of your compounds against the known target, using multiple concentrations and replicates to deliver the EC50.

  • Target receptor potency
  • Target enzyme inhibition

Computational

We predict a range of drug properties:

  • Octanol/water & water/gas log Ps
  • Log BB
  • Caco-2 and MDCK-MDR1 permeabilities
  • Log Khsa (human serum albumin binding)
  • Log IC50 for HERG K+ channel blockage

Discuss your needs in confidence…
If you have a drug discovery project that would benefit from Peakdale’s innovative and flexible resources, please contact us:

T +44(0)1298 816 700
F +44(0)1298 816 701
E enquiries@peakdale.co.uk