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In Vivo Approaches to Assessing the Blood–Brain Barrier

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

Abstract

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.

Keywords

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 

Abbreviations

%ID

Percentage of the injected dose

A

Capillary surface area (also denoted S in the literature)

AUC

Area under the concentration–time curve

BBB

Blood–brain barrier

BCRP

Breast cancer resistance protein

BCSFB

Blood–cerebrospinal fluid barrier

BEI

Brain efflux index

BUI

Brain uptake index

Cblood

Concentration of drug in blood

Cbrain

Concentration of drug in brain devoid of blood

Cinjectate

Concentration of drug in the injection solution

Cplasma

Concentration of drug in plasma

CLact_efflux

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

CLact_uptake

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

CLbulk_flow

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

CLin

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

CLmetabolism

Clearance caused by metabolism in the BBB or brain parenchyma

CLout

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

CLpassive

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

CSF

Cerebrospinal fluid

Ctot,brain,ss

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

Ctot,plasma,ss

Total plasma concentrations at steady state

Cu,brainISF

Concentration of drug in brain ISF

Cu,plasma

Unbound drug concentration in plasma

F

Blood flow

fu,brain

Fraction of unbound drug in whole brain homogenate

fu,plasma

Fraction of unbound drug in plasma

ICF

Intracellular fluid

ISF

Interstitial fluid

Jin

Rate of influx to the brain

Jout

Rate of efflux from the brain

Kin

Transfer constant at the BBB (a clearance term)

Kout

Overall loss constant (a clearance term)

Kp,brain

Partition coefficient of total drug between whole brain and plasma

Kp,uu,brain

Partition coefficient of unbound drug between brain ISF and plasma

LC-MS/MS

Liquid chromatography–tandem mass spectrometry

Mrp1

Multidrug resistance protein 1

P

Permeability

PET

Positron emission tomography

P-gp

P-glycoprotein

PA

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

Qbrain

Amount of drug in brain parenchyma devoid of blood

Qtot,brain

Amount of drug in brain parenchyma including capillary blood

Vblood

Physiological volume of blood in brain

Vbrain

Effective volume of distribution in the brain

Vi

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

Vu,brain

Volume of distribution of unbound drug in the brain

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

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

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