Revisiting atenolol as a low passive permeability marker

Area of Science:

• Pharmacokinetics
• Neuroscience
• Drug Transport

Background:

• Atenolol, a hydrophilic beta blocker, has served as a model for passive drug permeability across biological membranes like the blood-brain barrier (BBB).
• The distribution of S-atenolol, the active enantiomer, at the BBB has not been previously quantified at equilibrium to rule out transporter involvement.

Purpose of the Study:

• To determine if S-atenolol exhibits characteristics of low passive permeability at the BBB.
• To evaluate the role of active transport mechanisms in S-atenolol's brain distribution.

Main Methods:

• A rat microdialysis study monitored unbound S-atenolol concentrations in brain extracellular fluid (ECF) and plasma during intravenous infusion.
• A pharmacokinetic model estimated brain permeability clearance, and equilibrium dialysis assessed nonspecific binding in brain homogenate.

Main Results:

• The steady-state unbound S-atenolol concentration ratio in brain ECF to plasma (K_p,uu,brain) was significantly less than unity (3.5% ± 0.4%).
• S-atenolol demonstrated even distribution within brain parenchyma (V_{u, brain} = 0.69 ± 0.10 mL/g).
• Limited nonspecific binding was observed in brain homogenate (f_u,brain = 0.88 ± 0.07).

Conclusions:

• The low K_p,uu,brain indicates active efflux of S-atenolol at the BBB.
• S-atenolol should not be considered a reliable model for passive permeability studies of BBB transport.
• Findings suggest a need to re-evaluate S-atenolol's utility in studying intestinal absorption mechanisms as well.