Document Detail

Brain Penetration Assessment in vivo: a Reliable and Simple Method in Anesthetized Rats at Steady State.
MedLine Citation:
PMID:  24880048     Owner:  NLM     Status:  Publisher    
BACKGROUND: For CNS drugs, brain disposition is of critical importance during drug discovery. In-vitro methods are used early followed by more predictive in-vivo methods later on in the drug discovery process. Current in-vivo methods are costly, have long turnover times or don't measure brain disposition at steady state.
NEW METHOD: A new method to evaluate drug brain disposition in-vivo was developed in anaesthetized rats. Seven reference compounds were administered as an initial IV bolus (loading dose) followed by IV infusion for 4.5hours in order to obtain a steady state plasma concentration before brain sampling. The loading dose was estimated from a preliminary single dose IV pharmacokinetic study and was found to successfully bring plasma concentrations to steady state for compounds exhibiting either mono- or bi-compartmental pharmacokinetics.
RESULTS: Using this method, a steady state lasting at least 2h was obtained, thus making the in-vivo method robust with respect to differences in the pharmacokinetics and/or blood-to-brain equilibration rate of the compounds tested. The method produced highly reproducible results, with substantial advantages in terms of cost, turnaround time and animal welfare.
COMPARISON WITH EXISTING METHODS: The results agreed with those reported in other, more elaborate preclinical models and in humans, enabling brain disposition to be assessed in a simple, efficient and robust in-vivo model for new chemical entities.
CONCLUSIONS: Introducing the presented method in drug discovery allows brain disposition to be assessed earlier in the drug discovery pipeline and thus facilitate the selection of potent and penetrant CNS drugs.
A Andersen Claus; Perfetti Paolo; Nibbio Martina; Bellini Marta; Angelini Roberto; Fornasier Massenzio
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-5-28
Journal Detail:
Title:  Journal of neuroscience methods     Volume:  -     ISSN:  1872-678X     ISO Abbreviation:  J. Neurosci. Methods     Publication Date:  2014 May 
Date Detail:
Created Date:  2014-5-31     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7905558     Medline TA:  J Neurosci Methods     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 Elsevier B.V. All rights reserved.
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