Progress in brain penetration evaluation in drug discovery and development.

Area of Science:

• Neuroscience and Pharmacology
• Drug Discovery and Development

Background:

• Brain penetration is critical for central nervous system (CNS) drug efficacy.
• Kinetics involve extent (steady-state free brain/plasma ratio) and time to equilibrium.
• Blood-brain barrier (BBB) transport significantly influences drug distribution.

Purpose of the Study:

• To review strategies for optimizing drug brain penetration in CNS drug discovery.
• To highlight the role of efflux transporters, particularly P-glycoprotein (P-gp), at the BBB.
• To propose methods for managing drug transporter interactions for CNS and non-CNS targets.

Main Methods:

• Literature review of strategies for optimizing brain penetration kinetics.
• Analysis of the impact of efflux transport and passive permeability on BBB crossing.
• Evaluation of the in vivo significance of P-gp and other BBB drug transporters.

Main Results:

• Low efflux transport at the BBB is key for optimizing the extent of brain penetration.
• P-glycoprotein (P-gp) is the primary identified transporter limiting brain penetration of its substrates in vivo.
• Drug-drug interactions at the BBB via P-gp modulation (inhibition/induction) are possible.

Conclusions:

• CNS drug discovery should prioritize compounds with low P-gp substrate activity.
• Moderate P-gp substrates may be considered for CNS targets with high unmet need and safety margins.
• Utilizing P-gp substrates for non-CNS targets can mitigate CNS side effects.