title: Drug equilibration across the blood-brain barrier--pharmacokinetic considerations based on the microdialysis method.
abstract: OBJECTIVE
  The purpose of the study was to investigate the influence of different rates of transport into and out of the brain, including passive and active transport, on unbound brain concentrations and profile in relation to the blood concentration profile. Special emphasis is put on hydrophilic drugs.
  
  
  METHODS
  Simulations were performed with a model including one body compartment and one brain compartment, with linear or saturable transport into and out of the brain. Comparisons were made with experimental results from microdialysis (MD) studies.
  
  
  RESULTS
  Three features were evident when combining the MD results: 1) equilibration across the blood-brain barrier (BBB) is rapid, 2) half-life is similar in brain and blood for most drugs, and 3) unbound brain concentrations seldom reach the level of unbound blood concentrations. A low concentration ratio brain:blood is not mainly caused by a low influx, but rather by different influx and efflux clearances. Active transport out of the brain can explain the results, but also active transport into the brain under certain conditions. A small volume of distribution in brain vs. that in the rest of the body contributes to a rapid equilibration and similar half-lives.
  
  
  CONCLUSIONS
  Assumptions of slow equilibration of hydrophilic drugs and similar unbound concentrations across the BBB at steady state are contradicted. The results are more in line with recent findings on the presence of P-glycoprotein and other transport mechanisms at the BBB. Non-passive transport across the BBB seems to be the case for almost all drugs studies with MD so far.
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, University of Uppsala, Sweden. Margareta.Hammarlund-Udenaes@biof.uu.se
authors.forename: M
authors.initials: M
authors.lastname: Hammarlund-Udenaes
authors.forename: L K
authors.initials: LK
authors.lastname: Paalzow
authors.forename: E C
authors.initials: EC
authors.lastname: de Lange
mesh_terms: D001693:Biological Transport, Active; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D006801:Humans; D017551:Microdialysis; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics
chemical_list: D004364:Pharmaceutical Preparations