In Vivo Approaches to Assessing the Blood–Brain Barrier

  • Margareta Hammarlund-UdenaesEmail author
Part of the Topics in Medicinal Chemistry book series (TMC, volume 10)


Methods for in vivo assessment of blood-brain barrier (BBB) transport are presented, with their advantages and disadvantages. The methods described are brain uptake index, the i.v. injection technique, in situ brain perfusion, brain efflux index, % injected dose, microdialysis, CSF sampling and positron emission tomography, and the combinatorial mapping of unbound drug partitioning across the BBB. The methods are put into a pharmacokinetic context by delineating the type of readings that they give, be it the rate of transport across the BBB or the extent of transport of total drug (unbound and bound), or of the unbound drug.


Brain uptake index i.v. injection technique In situ brain perfusion Brain efflux index Microdialysis CSF sampling Positron emission tomography Fraction unbound in the brain Brain homogenate method Brain slice technique Volume of distribution of unbound drug in the brain 



Percentage of the injected dose


Capillary surface area (also denoted S in the literature)


Area under the concentration–time curve


Blood–brain barrier


Breast cancer resistance protein


Blood–cerebrospinal fluid barrier


Brain efflux index


Brain uptake index


Concentration of drug in blood


Concentration of drug in brain devoid of blood


Concentration of drug in the injection solution


Concentration of drug in plasma


Active efflux clearance at the BBB (sum of all processes contributing to active efflux)


Active uptake clearance at the BBB (sum of all processes contributing to active uptake)


Clearance caused by bulk flow of fluid from brain ISF to CSF


Influx clearance i.e. the net influx given all transport processes at the BBB


Clearance caused by metabolism in the BBB or brain parenchyma


Efflux clearance, i.e., the net efflux given all transport and metabolism processes from the brain ISF


Passive clearance (permeability surface area product) across the BBB being the same in both directions


Cerebrospinal fluid


Total brain concentrations at steady state (whole brain minus capillary blood)


Total plasma concentrations at steady state


Concentration of drug in brain ISF


Unbound drug concentration in plasma


Blood flow


Fraction of unbound drug in whole brain homogenate


Fraction of unbound drug in plasma


Intracellular fluid


Interstitial fluid


Rate of influx to the brain


Rate of efflux from the brain


Transfer constant at the BBB (a clearance term)


Overall loss constant (a clearance term)


Partition coefficient of total drug between whole brain and plasma


Partition coefficient of unbound drug between brain ISF and plasma


Liquid chromatography–tandem mass spectrometry


Multidrug resistance protein 1




Positron emission tomography




Permeability surface area product (mL min−1 g brain−1) also denoted PS


Amount of drug in brain parenchyma devoid of blood


Amount of drug in brain parenchyma including capillary blood


Physiological volume of blood in brain


Effective volume of distribution in the brain


Effective vascular space in which a compound can be found including endothelial cell binding and accumulation and intravascular volume


Volume of distribution of unbound drug in the brain


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© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Translational PKPD Group, Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden

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