Revisiting atenolol as a low passive permeability marker

Fluids and Barriers of the CNS
Xiaomei ChenMargareta Hammarlund-Udenaes

Abstract

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., Kp,uu,brain) was 3.5% ± 0.4%, a value much less than unity. The unbound volume of distribution in brain (Vu, brain) of S-atenolol was also calculated as 0.69 ± 0.10 mL/g brain, indicating that S-atenolol i...Continue Reading

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Citations

Mar 27, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Dennis A Smith, Malcolm Rowland
Aug 18, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Faleh AlqahtaniUlrich Bickel
Jan 15, 2021·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Ekram Ahmed ChowdhuryLuca Cucullo
Jun 19, 2021·Journal of Pharmacokinetics and Pharmacodynamics·Mohammed A A SalehElizabeth C M De Lange
Aug 15, 2021·Expert Review of Neurotherapeutics·Bruno A Marichal-CancinoCarlos M Villalón

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Methods Mentioned

BETA
equilibrium dialysis

Software Mentioned

GraphPad Prism
R
PsN
NONMEM
Masslynx
Xpose 4
R Foundation for Statistical

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