Do we need to optimize plasma protein and tissue binding in drug discovery?

Area of Science:

• Pharmacology
• Drug Metabolism and Pharmacokinetics
• Biochemistry

Background:

• * It is widely assumed that only unbound drug molecules interact with targets.
• * Achieving high unbound drug concentrations is often pursued by minimizing plasma and tissue protein binding.
• * This approach is based on the premise that reduced binding directly correlates with increased free drug levels.

Purpose of the Study:

• * To challenge the conventional assumption that low protein binding is key to high unbound drug concentrations.
• * To investigate the actual determinants of unbound plasma and tissue drug concentrations in vivo.
• * To re-evaluate the role of protein binding in drug discovery and development.

Main Methods:

• * Theoretical analysis of pharmacokinetic principles governing drug distribution.
• * Experimental validation using in vitro and in vivo models.
• * Examination of factors influencing hepatic intrinsic clearance and blood-tissue barrier transport.

Main Results:

• * Unbound plasma drug concentration is primarily determined by hepatic intrinsic clearance, not plasma protein binding, after oral administration.
• * Unbound tissue drug concentration depends on unbound plasma concentration and blood-tissue barrier transport, not tissue binding.
• * In vitro reduction of protein binding may not translate to increased in vivo unbound concentrations.

Conclusions:

• * Plasma and tissue protein binding are crucial for understanding pharmacokinetics and pharmacodynamics but should not be independently optimized.
• * Reducing hepatic clearance and blood-tissue barrier efflux are more effective strategies for increasing in vivo unbound drug concentrations.
• * A paradigm shift is needed in drug discovery, moving away from solely optimizing protein binding.