Revisiting atenolol as a low passive permeability marker

• Published in: Fluids and barriers of the CNS Vol. 14; no. 1; p. 30
• Main Authors: Chen, Xiaomei, Slättengren, Tim, de Lange, Elizabeth C M, Smith, David E, Hammarlund-Udenaes, Margareta
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31.10.2017; BioMed Central; BMC
• Subjects: Analysis; Atenolol; Blood-brain barrier; Dosage and administration; Enantiomers; Epithelium; Equilibrium dialysis; Glycoproteins; Intestinal absorption; Intestine; Intravenous administration; K-brain; K-uu; Lipophilicity; Membrane permeability; Microdialysis; Parenchyma; Passive permeability; Permeability; Pharmacokinetics; Rodents; Transporters; Unbound equilibrium partition coefficient (K-p; Unbound equilibrium partition coefficient (Kp,uu,brain); Unbound volume of distribution in brain (V-u; Unbound volume of distribution in brain (Vu,brain); V-brain; Microdialysis; Unbound volume of distribution in brain (Vu,brain); Transporters; Passive permeability; Atenolol; Pharmacokinetics; Unbound equilibrium partition coefficient (Kp,uu,brain); Lipophilicity; Blood–brain barrier
• ISSN: 2045-8118; 2045-8118
• DOI: 10.1186/s12987-017-0078-x

Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and the intestinal epithelium. However, the extent of S-atenolol (the active enantiomer) distribution in brain has never been evaluated, at equilibrium, to confirm that no transporters are involved in its transport at the BBB. To assess whether S-atenolol, in fact, depicts the characteristics of a low passive permeable drug at the BBB, a microdialysis study was performed in rats to monitor the unbound concentrations of S-atenolol in brain extracellular fluid (ECF) and plasma during and after intravenous infusion. A pharmacokinetic model was developed, based on the microdialysis data, to estimate the permeability clearance of S-atenolol into and out of brain. In addition, the nonspecific binding of S-atenolol in brain homogenate was evaluated using equilibrium dialysis. The steady-state ratio of unbound S-atenolol concentrations in brain ECF to that in plasma (i.e., K ) was 3.5% ± 0.4%, a value much less than unity. The unbound volume of distribution in brain (V ) of S-atenolol was also calculated as 0.69 ± 0.10 mL/g brain, indicating that S-atenolol is evenly distributed within brain parenchyma. Lastly, equilibrium dialysis showed limited nonspecific binding of S-atenolol in brain homogenate with an unbound fraction (f ) of 0.88 ± 0.07. It is concluded, based on K being much smaller than unity, that S-atenolol is actively effluxed at the BBB, indicating the need to re-consider S-atenolol as a model drug for passive permeability studies of BBB transport or intestinal absorption.