Avoiding physicochemical artefacts in early ADME-Tox experiments

Area of Science:

• Drug discovery and development
• Pharmacokinetics and drug metabolism
• Biophysical chemistry

Background:

• Physicochemical properties significantly impact high-throughput screening (HTS) and ADME-Tox assessments.
• Artefacts such as high lipophilicity, poor solubility (aqueous and DMSO), aggregation, and non-specific binding can compromise experimental data.
• These issues can lead to misinterpretation of drug candidate efficacy and safety profiles.

Purpose of the Study:

• To review the impact of common physicochemical artefacts in HTS and ADME-Tox.
• To propose experimental strategies for mitigating these artefacts.
• To maintain the efficiency of experimental processes during artefact control.

Main Methods:

• Literature review focusing on physicochemical properties and their effects on HTS and ADME-Tox assays.
• Analysis of common artefacts including lipophilicity, solubility, aggregation, and protein/phospholipid binding.
• Identification and synthesis of experimental techniques to minimize artefact occurrence.

Main Results:

• High lipophilicity, low solubility, aggregation, and non-specific binding are identified as key confounding factors.
• These artefacts can distort results from individual assays and aggregate interpretations.
• Experimental strategies can effectively reduce the frequency and magnitude of these artefacts.

Conclusions:

• Careful control of physicochemical properties is crucial for reliable HTS and ADME-Tox data.
• Implementing suggested experimental strategies can improve data quality without sacrificing throughput.
• Minimizing artefacts ensures more accurate drug candidate assessment in early-stage development.