Efflux transporters in the blood-brain interfaces--in vitro and in vivo methods and correlations.

CímEfflux transporters in the blood-brain interfaces--in vitro and in vivo methods and correlations.
Publication TypeJournal Article
Year of Publication2012
AuthorsKrajcsi P, Jani M, Tóth B, Erdő F, Kis E, Beéry E, Sziráki I
JournalExpert Opinion on Drug Metabolism & Toxicology
Volume8
Start Page419
Issue4
KulcsszavakABCB1, ABCC4, ABCG2, BCRP, blood–brain barrier, blood–cerebrospinal fluid barrier, brain microdialysis, efflux transporters, MRP4, P-glycoprotein
Abstract

INTRODUCTION:
Sufficient brain exposure is crucial to the success of CNS drugs. The twofold greater attrition rate in clinical development of CNS drugs over the respective attrition rate of non-CNS drugs is due to lack of efficacy. It is generally thought that poor brain exposure is at least partly responsible for this, as the concentration-time profile at the brain target site is critical for efficacy. Efflux transporters in the blood-brain interfaces play a crucial role in modulation of permeability of drugs across these interfaces. Validation of preclinical tools to correctly predict brain exposure in humans is essential.

AREAS COVERED:
This review summarizes in vitro and in vivo tools to detect and characterize interactions of drugs with efflux transporters relevant to blood-brain interfaces. Furthermore, the article discusses the strengths and weaknesses of these methods and the limitations of their application, in addition to covering in vitro - in vivo correlations.

EXPERT OPINION:
A more detailed validation of in vitro efflux transporter assays employing primary brain endothelial cultures is needed. This should go along with mapping uptake transporters expressed in the blood-brain interfaces. With the availability of specific inhibitors, utilization of in vivo methods such as brain microdialysis is increasing. Once transporter-humanized mice are available, we may witness a further increase in applications of in vivo methods.

Webcímhttp://www.ncbi.nlm.nih.gov/pubmed/22394316
DOI10.1517/17425255.2012.668184