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Revisiting atenolol as a low passive permeability marker
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Translational PKPD)
Leiden Acad Ctr Drug Res, Dept Pharmacol, Leiden, Netherlands..
Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
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2017 (English)In: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 14, article id 30Article in journal (Refereed) Published
Abstract [en]

Background: 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.

Methods: 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.

Results: The steady-state ratio of unbound S-atenolol concentrations in brain ECF to that in plasma (i.e., -K-p,K-uu,K-brain) was 3.5% +/- 0.4%, a value much less than unity. The unbound volume of distribution in brain -(V-u,V- brain) 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(u, brain)) of 0.88 +/- 0.07.

Conclusions: It is concluded, based on -K-p,K-uu,K-brain 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.

Place, publisher, year, edition, pages
2017. Vol. 14, article id 30
Keywords [en]
Atenolol, Blood-brain barrier, Microdialysis, Unbound equilibrium partition coefficient (K-p, K-uu, K-brain), Unbound volume of distribution in brain (V-u, V-brain), Passive permeability, Transporters, Pharmacokinetics, Lipophilicity
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-341367DOI: 10.1186/s12987-017-0078-xISI: 000414175000001PubMedID: 29089037OAI: oai:DiVA.org:uu-341367DiVA, id: diva2:1181282
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-02-08Bibliographically approved

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Chen, XiaomeiHammarlund-Udenaes, Margareta
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