Comparison of in vitro cell models in predicting in vivo brain entry of drugs

Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood–brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient ( P app) dete...

Full description

Saved in:
Bibliographic Details
Published in:International journal of pharmaceutics 2010-12, Vol.402 (1), p.27-36
Main Authors: Hakkarainen, Jenni J., Jalkanen, Aaro J., Kääriäinen, Tiina M., Keski-Rahkonen, Pekka, Venäläinen, Tetta, Hokkanen, Juho, Mönkkönen, Jukka, Suhonen, Marjukka, Forsberg, Markus M.
Format: Article
Language:English
Subjects:
Animals
BBMEC
Biological and medical sciences
Biological Transport
Blood-Brain Barrier - metabolism
Blood–brain barrier
Brain - metabolism
Caco-2
Caco-2 Cells
Cattle
Cell Line
Dogs
General pharmacology
Humans
In vivo relevance
Male
MDCKII-MDR1
Medical sciences
Microdialysis - methods
Models, Biological
Permeability
Pharmaceutical Preparations - metabolism
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Rats
Rats, Wistar
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Although several in vitro models have been reported to predict the ability of drug candidates to cross the blood–brain barrier, their real in vivo relevance has rarely been evaluated. The present study demonstrates the in vivo relevance of simple unidirectional permeability coefficient ( P app) determined in three in vitro cell models (BBMEC, Caco-2 and MDCKII-MDR1) for nine model drugs (alprenolol, atenolol, metoprolol, pindolol, entacapone, tolcapone, baclofen, midazolam and ondansetron) by using dual probe microdialysis in the rat brain and blood as an in vivo measure. There was a clear correlation between the P app and the unbound brain/blood ratios determined by in vivo microdialysis (BBMEC r = 0.99, Caco-2 r = 0.91 and MDCKII-MDR1 r = 0.85). Despite of the substantial differences in the absolute in vitro P app values and regardless of the method used (side-by-side vs. filter insert system), the capability of the in vitro models to rank order drugs was similar. By this approach, thus, the additional value offered by the true endothelial cell model (BBMEC) remains obscure. The present results also highlight the need of both in vitro as well as in vivo methods in characterization of blood–brain barrier passage of new drug candidates.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2010.09.016