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Evaluation of Drugs with Specific Organ Toxicities in Organ Specific Cell Lines.
MedLine Citation:
PMID:  22166485     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Safety attrition of drugs during preclinical development as well as in late stage clinical trials continues to be a challenge for the pharmaceutical industry for patient welfare and financial reasons. Hepatic-, cardiac- and nephro-toxicity remain the main reasons for compound termination. In recent years, efforts have been made to identify such liabilities earlier in the drug development process, through utilization of in silico and cytotoxicity models. Several publications have aimed to predict specific organ toxicities. For example two large scale evaluations of hepatotoxic compounds have been conducted. In contrast, only small cardio and nephrotoxic compound sets have been evaluated. Here, we investigated the utility of a hepatic, cardiac and kidney-derived cell lines to 1. accurately predict cytotoxicity and 2. to accurately predict specific organ toxicities. We tested 273 hepatotoxic, 191cardiotoxic, and 85 nephrotoxic compounds in HepG2 (hepatocellular carcinoma), H9c2 (embryonic myocardium), and NRK-52E (kidney proximal tubule) cells for their cytotoxicity. We found that the majority of compounds, regardless of their designated organ toxicities, had similar effects in all three cell lines. Only approximately 5% of compounds showed differential toxicity responses in the cell lines with no obvious correlation to the known in vivo organ toxicity. Our results suggest that from a general screening perspective different cell lines have relatively equal value in assessing general cytotoxicity and that specific organ toxicity cannot be accurately predicted using such a simple approach. Select organ toxicity potentially results from compound accumulation in a particular tissue, cell types within organs, metabolism and off-target effects. Our analysis however demonstrates that the prediction can be improved significantly when human C(max) values are incorporated.
Authors:
Zhiwu Lin; Yvonne Will
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-13
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  -     ISSN:  1096-0929     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Compound Safety Prediction, Word Wide Medicinal Chemistry, Pfizer Global R&D, Groton, CT.
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