P-gp inhibition potential in cell-based models: which "calculation" method is the most accurate?

Area of Science:

• Pharmacology
• Drug Discovery
• Biochemistry

Background:

• P-glycoprotein (P-gp) plays a crucial role in drug transport and disposition.
• Accurate assessment of P-gp inhibition potential is vital for drug development.
• Existing calculation methods for P-gp inhibition vary, potentially leading to different conclusions.

Purpose of the Study:

• To directly compare four distinct calculation methods for assessing P-gp inhibition potential.
• To evaluate the impact of different calculation methods on determining a compound's P-gp inhibition profile.
• To identify the most suitable method for early-stage drug discovery screening.

Main Methods:

• Utilized experimental data from approximately 60 diverse compounds.
• Performed bidirectional digoxin transport studies (P-gp substrate probe) with and without test compounds (10 µM).
• Applied four different calculation methods to the same raw bidirectional permeability data.

Main Results:

• Significantly different P-gp inhibition potentials were obtained using the same experimental dataset across the four methods.
• The choice of calculation method led to divergent conclusions regarding compounds' inhibition potential.
• Method 3 (inhibition of B to A digoxin permeability) showed high correlation with Method 1 (bidirectional inhibition).

Conclusions:

• Method 3 is recommended for high-throughput screening in early drug discovery due to its efficiency and reliability.
• Method 3 effectively categorizes compounds as non-inhibitors, moderate inhibitors, or potent inhibitors.
• Method 1 may be more suitable for detailed mechanistic studies in later stages of drug discovery and development.