Background: Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability\nof biological membranes such as the bloodââ?¬â??brain barrier (BBB) and the intestinal epithelium. However, the extent of\nS-atenolol (the active enantiomer) distribution in brain has never been evaluated, at equilibrium, to confirm that no\ntransporters are involved in its transport at the BBB.\nMethods: To assess whether S-atenolol, in fact, depicts the characteristics of a low passive permeable drug at the\nBBB, a microdialysis study was performed in rats to monitor the unbound concentrations of S-atenolol in brain extracellular\nfluid (ECF) and plasma during and after intravenous infusion. A pharmacokinetic model was developed, based\non the microdialysis data, to estimate the permeability clearance of S-atenolol into and out of brain. In addition, the\nnonspecific binding of S-atenolol in brain homogenate was evaluated using equilibrium dialysis.\nResults: The steady-state ratio of unbound S-atenolol concentrations in brain ECF to that in plasma (i.e., Kp,uu,brain) was\n3.5% Ã?± 0.4%, a value much less than unity. The unbound volume of distribution in brain (Vu, brain) of S-atenolol was\nalso calculated as 0.69 Ã?± 0.10 mL/g brain, indicating that S-atenolol is evenly distributed within brain parenchyma.\nLastly, equilibrium dialysis showed limited nonspecific binding of S-atenolol in brain homogenate with an unbound\nfraction (fu,brain) of 0.88 Ã?± 0.07.\nConclusions: It is concluded, based on Kp,uu,brain being much smaller than unity, that S-atenolol is actively effluxed\nat the BBB, indicating the need to re-consider S-atenolol as a model drug for passive permeability studies of BBB transport\nor intestinal absorption.
Loading....