Document Detail


The Use of Micropatterned Co-cultures to Detect Compounds that Cause Drug induced Liver Injury in Humans.
MedLine Citation:
PMID:  23152190     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Since drug induced liver injury (DILI) remains a major reason for late stage drug attrition, predictive assays are needed that can be deployed throughout the drug discovery process Clinical DILI can be predicted with a sensitivity of ~50% and a false positive rate of ~5% using 24 hour cultures of primary sandwich cultured human hepatocytes and imaging of four cell injury endpoints (Xu et al., 2008). We hypothesized that long-term drug dosing in a stable model of primary hepatocytes (micropatterned co-cultures or MPCCs) could provide for increased predictivity over short-term dosing paradigms. We used MPCCs with either primary human or rat hepatocytes to understand possible species differences along with standard end-points (glutathione levels, ATP levels, albumin and urea secretion) to test 45 drugs either known or not known to cause clinical DILI. Human MPCCs correctly detected 23 of 35 compounds known to cause DILI (65.7% sensitivity) with a false positive rate of 10% for the 10 negative compounds tested. Rat MPCCs correctly detected 17 of 35 DILI compounds (48.6% sensitivity) and had a higher false positive rate than human MPCCs (20% versus 10%). For drugs with the most DILI concern, human MPCCs displayed a sensitivity of 100%. Furthermore, MPCCs were able to detect relative clinical toxicities of structural drug analogs. In conclusion, MPCCs showed superiority over conventional short-term cultures for predictions of clinical DILI and human MPCCs were more predictive for human liabilities than their rat counterparts.
Authors:
Salman R Khetani; Chitra Kanchagar; Okechukwu Ukairo; Stacy Krzyzewski; Amanda Moore; Julianne Shi; Simon Aoyama; Michael Aleo; Yvonne Will
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-14
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  -     ISSN:  1096-0929     ISO Abbreviation:  Toxicol. Sci.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Mechanical and Biomedical Engineering, Colorado State University, Fort Collins, CO.
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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