RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Revisiting atenolol as a low passive permeability marker
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. (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..
Vise andre og tillknytning
2017 (engelsk)Inngår i: Fluids and Barriers of the CNS, ISSN 2045-8118, E-ISSN 2045-8118, Vol. 14, artikkel-id 30Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2017. Vol. 14, artikkel-id 30
Emneord [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
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-341367DOI: 10.1186/s12987-017-0078-xISI: 000414175000001PubMedID: 29089037OAI: oai:DiVA.org:uu-341367DiVA, id: diva2:1181282
Tilgjengelig fra: 2018-02-08 Laget: 2018-02-08 Sist oppdatert: 2018-02-08bibliografisk kontrollert

Open Access i DiVA

fulltext(1715 kB)9 nedlastinger
Filinformasjon
Fil FULLTEXT01.pdfFilstørrelse 1715 kBChecksum SHA-512
26ba1b1678ef70b444e51ffdbd481b18df16b8647cb211ce28230e8962699dda5c84be651c0bed9686f05937076f47495e144482b41a9f753a7159b069da054f
Type fulltextMimetype application/pdf

Andre lenker

Forlagets fulltekstPubMed

Søk i DiVA

Av forfatter/redaktør
Chen, XiaomeiHammarlund-Udenaes, Margareta
Av organisasjonen
I samme tidsskrift
Fluids and Barriers of the CNS

Søk utenfor DiVA

GoogleGoogle Scholar
Totalt: 9 nedlastinger
Antall nedlastinger er summen av alle nedlastinger av alle fulltekster. Det kan for eksempel være tidligere versjoner som er ikke lenger tilgjengelige

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 26 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf