Document Detail

In vitro measurement of drug efficiency index to aid early lead optimization.
MedLine Citation:
PMID:  22930396     Owner:  NLM     Status:  Publisher    
The concepts of drug efficiency (D(eff) ) and Drug Efficiency Index (DEI) have been recently introduced as useful parameters to optimize the absorption, distribution, metabolism, elimination/excretion, and toxicity properties and in vivo efficacy potential of molecules during lead optimization and at pre-clinical stages. The available free drug concentration relative to dose depends on the compound's bioavailability, clearance, and the nonspecific binding to proteins and phospholipids. In this paper, we have demonstrated, using the data of over 115 known drug molecules, that the nonspecific binding can be determined in vitro very efficiently using biomimetic high-performance liquid chromatography measurements. DEI can therefore be estimated from in vitro measurements. The data show that high in vitro DEI values can be associated with lower efficacious dose. A strategy is described of how to use the DEI parameter during early lead optimization. An example is given to highlight the advantages of optimizing on DEI value rather than on potency alone. In order to facilitate the in silico compound design, correlation between in vitro DEI and in silico ligand efficiency parameters such as ligand lipophilicity efficiency has been revealed, suggesting the potential use of these efficiency-related parameters across lead optimization. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Klara Valko; Elisabetta Chiarparin; Shenaz Nunhuck; Dino Montanari
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-28
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  -     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-29     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Analytical Chemistry, Platform Technology and Science, GlaxoSmithKline, Stevenage, UK.
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