Drug-protein binding and blood-brain barrier permeability

Area of Science:

• Pharmacokinetics
• Neuroscience
• Biomedical Engineering

Background:

• The blood-brain barrier (BBB) restricts drug entry into the brain.
• Drug permeability across the BBB depends on both unbound and protein-bound fractions.
• Accurate assessment of BBB permeability is crucial for developing effective therapeutics.

Purpose of the Study:

• To measure the permeability surface area (PS) product of the BBB for various drugs.
• To compare the unbound drug fraction in vitro with the apparent exchangeable fraction in vivo.
• To evaluate the utility of the in situ perfusion method for estimating BBB permeability.

Main Methods:

• In situ perfusion and intracarotid artery injection methods were used to measure BBB permeability.
• Ultrafiltration was employed to determine the unbound drug fraction in vitro.
• Varying bovine serum albumin (BSA) concentrations were used to estimate apparent exchangeable fractions in vivo.

Main Results:

• Apparent exchangeable fractions in vivo were consistently higher than in vitro unbound fractions for all tested drugs.
• For diazepam and S-312-d, apparent exchangeable fractions were 8 and 38 times higher, respectively, than their unbound fractions.
• The in situ perfusion method provided similar apparent exchangeable fraction estimates to the intracarotid artery injection method.

Conclusions:

• Protein binding significantly influences drug permeation across the BBB, with dissociation contributing substantially to the apparent exchangeable fraction.
• The in situ perfusion method is a viable technique for measuring BBB permeability, especially for low-permeability substances.
• Understanding these dynamics is essential for optimizing drug design and delivery for central nervous system disorders.