Strategies for absorption screening in drug discovery and development

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Drug Discovery and Development
• Computational Chemistry

Background:

• Accurate prediction of drug absorption is crucial for successful drug discovery.
• Evaluating absorption potential early minimizes late-stage failures.
• Diverse methods exist, each with unique strengths and limitations.

Purpose of the Study:

• To provide a comprehensive overview of current drug absorption evaluation techniques.
• To discuss the utility of various models across drug discovery and development phases.
• To highlight the integration of different methods for enhanced prediction accuracy.

Main Methods:

• In silico modeling (e.g., iDEA) for early prediction based on structure.
• Artificial membrane assays (e.g., filter-IAM) for high-throughput screening.
• In vitro cell-based models (e.g., Caco-2, Ussing chamber) for mechanistic insights and active transport.
• In situ rat intestinal perfusion for absorption and metabolism studies.
• In vivo bioavailability studies in animals.

Main Results:

• In silico models offer initial predictions, improved by incorporating experimental data.
• Artificial membranes provide rapid permeability classification but lack active transport simulation.
• Cell-based models (Caco-2) are essential for studying efflux mechanisms like P-glycoprotein (PgP) and drug-drug interactions.
• In situ and in vivo studies provide integrated absorption and metabolism data, with in vivo studies estimating bioavailability.

Conclusions:

• A tiered approach, integrating in silico, in vitro, in situ, and in vivo methods, is optimal for robust drug absorption assessment.
• Early and accurate prediction of absorption potential streamlines drug development.
• Understanding limitations of each model, such as missing active transport in artificial membranes, is key to appropriate method selection.